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TW200539856A - Therapeutic compounds - Google Patents

Therapeutic compounds Download PDF

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Publication number
TW200539856A
TW200539856A TW094115325A TW94115325A TW200539856A TW 200539856 A TW200539856 A TW 200539856A TW 094115325 A TW094115325 A TW 094115325A TW 94115325 A TW94115325 A TW 94115325A TW 200539856 A TW200539856 A TW 200539856A
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TW
Taiwan
Prior art keywords
amino
group
phenyl
carbonyl
alkyl
Prior art date
Application number
TW094115325A
Other languages
Chinese (zh)
Inventor
Shu-Juan Jin
zi-ping Liu
Claire Milburn
Miroslaw Tomaszewski
Christopher Walpole
Zhongyong Wei
Hua Yang
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Astrazeneca Ab
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Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of TW200539856A publication Critical patent/TW200539856A/en

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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4, m and n are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

200539856 九、發明說明： 【發明所屬之技術領域】 本發明係關於治療化合物，含有此等化合物之醫藥組合 物，其製程及其用途。特定言之，本發明係關於可有效治 療疼痛、癌症、多發性硬化、巴金生氏病、亨丁頓氏舞蹈 症、阿耳滋海默氏疾㉟、焦慮病症、胃腸病症及/或心企管 病症之化合物。 _ 【先前技術】 多年來’疼痛處理已經是一項重要之研究領域。一般已 習知的是，類大莱誓受體（例如CBi受體、CB2受體）配位體， 包括催動劑、拮抗劑及逆催動劑，其係在多種動物模式中， 經由與CBA/或CB2受體交互作用，而產生疼痛之舒解。一 ’又而。CBi又體主要係位於中樞神經系統中，然而a%受 體主要係位於末梢中，且主要係受限制於衍生自免疫系統 之細胞與組織。 籲 隹」CBl又體催動劑譬如四氫大蔴油醇（y-THC)與阿 那達酿胺(anadamide)可用於動物之抗感受傷害模式中，但其 傾向於施加不想要之CNS副作用，·精神活性副作用、 濫用可能性、藥物賴藥性與耐藥性等。已知此等不想要之 副作用係藉由位於CNS中之％受體所媒介。但是，有數條 據才曰出作用於末梢位置或具有有限cns曝露之⑽催動200539856 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to therapeutic compounds, pharmaceutical compositions containing these compounds, their processes and uses. In particular, the present invention relates to effective treatments for pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety disorders, gastrointestinal disorders, and / or cardiac management Compounds of disorders. _ [Previous technique] Pain management has been an important research area for many years. It is generally known that the ligands for Dalai Lama receptors (such as CBi receptor, CB2 receptor), including activators, antagonists and inverse activators, are in a variety of animal models through CBA / or CB2 receptors interact to produce pain relief. One ’and then again. CBi is mainly located in the central nervous system, however, a% of the receptors are mainly located in the periphery, and are mainly restricted to cells and tissues derived from the immune system. "Bei" CBl stimulants such as tetrahydrocannabinol (y-THC) and anadamide can be used in the antinociceptive mode of animals, but they tend to exert unwanted CNS side effects, · Psychoactive side effects, the possibility of abuse, drug dependence and drug resistance. These unwanted side effects are known to be mediated by% receptors located in the CNS. However, there are several data that indicate that the urgency is limited to the peripheral position or has limited cns exposure.

劑’可以極經改良之敕yfg)、、签躺咖A 艮芡正個活體内作用形態處理人類或動物 中之疼痛。 因此，有-項對於新穎％受體配位體譬如催動劑之需 101539 200539856 求，其可用於處理疼痛或治療其他相關病徵或疾病，伴隨 著經降低或最少之不想要CNS副作用。 【發明内容】 具體實施例之描述 本發明係提供CBi受體配位體，其可用於治療疼痛及/或 其他相關病徵或疾病。 除非在本專利說明書内另有指定，否則本專利說明書中 • 所使用之命名法，大致上係按照有譏允學命名法，瘦遂 忒及C A尽F及//，Pergamon出版社，〇xf〇rd，1979中所述之實例 與規則’其係併於本文，參考其舉例之化學結構名稱及關 於命名化學結構之規則。Agent ′ can be extremely modified (yfg), and lie down coffee A gen 芡 is in vivo action form to deal with pain in humans or animals. Therefore, there is a need for novel% receptor ligands such as activators 101539 200539856, which can be used to treat pain or treat other related signs or diseases, with reduced or minimal unwanted CNS side effects. [Summary of the Invention] Description of Specific Embodiments The present invention provides CBi receptor ligands, which can be used to treat pain and / or other related signs or diseases. Unless otherwise specified in this patent specification, the nomenclature used in this patent specification is generally in accordance with the nomenclature of nomenclature, thin and thin, and CA, F and //, Pergamon Publishing House, 0xf The examples and rules described in Ord, 1979 are incorporated herein by reference to the names of chemical structures and the rules for naming chemical structures.

Cm-n或1’cm_n基團”術語，單獨或作為字首使用，係指具 有m至n個碳原子之任何基團。 八 -詞’單獨或作為字尾或字首使用，係指僅包含碳 與氳原子且至高14個碳原子之任何結構。 • /烴基團"或"烴基"術語，單獨或作為字尾或字首使用， 係指由於自烴移除一或多個氫所造成之任何結構。 "烧基"一詞’單獨或作為字尾或字首使用，係指包含ι 至約12個碳原子之單價直鏈或分枝鏈烴基。烷基之說明 例，包括但不限於〇1_6烧基’譬如甲基、乙基、丙基、異 丙基、2-甲基+丙基、2_曱基：丙基、2_甲基丁基、甲基 丁基2-甲基_3-丁基、2,2-二甲基-1-丙基、2_甲基_卜戊基、 3- 甲基小戊基、4_甲基小戊基、2_甲基_2_戊基、3_甲基冬戊基、 4- 甲基_2_戊基、2,2_二甲基小丁基、&二甲基·卜丁基、2_乙 101539 200539856 基小丁基、丁基、異丁基、第三·丁基、戊基、異戊基、新 戊基及己基，與較長之烷基，譬如庚基與辛基。烷基可為 未經取代，或被一或兩個適當取代基取代。 π次烷基”一詞，單獨或作為字尾或字首使用，係指包含 1至約12個碳原子之二價直鏈或分枝鏈烴基，其係用以使兩 種結構連結在一起。 ”烯基”一詞，單獨或作為字尾或字首使用，係指具有至 • 少一個碳-碳雙鍵，且包含至少2個至高達約12個碳原子之 單價直鏈或分枝鏈烴基。烯基之雙鍵可為未共軛或經共軛 至另一個不飽和基團。適當烯基包括但不限於c2 6烯基， 譬如乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯 基、戊一婦基、己二烯基、2-乙基己烯基、2_丙基_2_丁烯基、 4-(2-甲基-3-丁烯）-戊烯基。烯基可為未經取代，或被一或兩 個適當取代基取代。 π炔基π —詞，單獨或作為字尾或字首使用，係指具有至 • 少一個碳-碳參鍵，且包含至少2個至高達約12個碳原子之 單價直鏈或分枝鏈烴基。炔基之參鍵可為未共軛或經共輛 至另一個不飽和基團。適當炔基包括但不限於c2 _ 6炔基， 譬如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙 快基、4-曱基-1·丁快基、4-丙基-2-戊快基及4-丁基-2-己炔基。 炔基可為未經取代，或被一或兩個適當取代基取代。 環烧基一詞’單獨或作為字尾或字首使用，係指包含 至少3個至高達約12個碳原子之飽和含單價環之烴基。環烷 基之實例包括但不限於C：3·7環烷基，譬如環丙基、環丁基、 101539 200539856 環戊基、環己基及環庚基，以及飽和環狀與雙環狀萜烯類。 環烷基可為未經取代，或被一或兩個適當取代基取代。環 烷基較佳為單環狀環或雙環狀環。 ”環烯基”一詞，單獨或作為字尾或字首使用，係指具有 至少一個碳-碳雙鍵，且包含至少3個至高達約12個碳原子 之含單價環烴基。 裏炔基"司，單獨或作為字尾或字首使用，係指具有The term "Cm-n or 1'cm_n group", used alone or as a prefix, refers to any group having m to n carbon atoms. The eight-word 'single or used as a suffix or prefix, means only Any structure containing carbon and rhenium atoms up to 14 carbon atoms. • / Hydrocarbon group " or " hydrocarbyl " term, used alone or as a suffix or prefix, refers to the removal of one or more from a hydrocarbon Any structure caused by hydrogen. The term "alkynyl" is used alone or as a suffix or prefix, and refers to a monovalent straight or branched chain hydrocarbon group containing ι to about 12 carbon atoms. Explanation of alkyl Examples include, but are not limited to, alkynyl groups such as methyl, ethyl, propyl, isopropyl, 2-methyl + propyl, 2-fluorenyl: propyl, 2-methylbutyl, methyl Butyl 2-methyl_3-butyl, 2,2-dimethyl-1-propyl, 2-methyl_pentyl, 3-methylpentyl, 4-methylpentyl, 2_methyl_2_pentyl, 3_methyl benzyl, 4-methyl_2_pentyl, 2,2-dimethyl small butyl, & dimethylbutyl, 2_ethyl 101539 200539856 small butyl, butyl, isobutyl, tert-butyl, pentyl , Isopentyl, neopentyl, and hexyl, and longer alkyls, such as heptyl and octyl. Alkyl can be unsubstituted or substituted with one or two suitable substituents. The term, used alone or as a suffix or prefix, refers to a divalent straight or branched chain hydrocarbon group containing from 1 to about 12 carbon atoms, which is used to link two structures together. The term "alkenyl", used alone or as a suffix or prefix, refers to a monovalent straight or branched chain having at least one carbon-carbon double bond and containing at least 2 to up to about 12 carbon atoms Alkyl. The double bond of an alkenyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkenyls include, but are not limited to, C2 6 alkenyl, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentyl, hexadienyl, 2-ethyl Hexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene) -pentenyl. An alkenyl can be unsubstituted or substituted with one or two suitable substituents. πalkynyl π — Word, used alone or as a suffix or prefix, refers to a monovalent straight or branched chain with at least one carbon-carbon parameter bond and containing at least 2 to up to about 12 carbon atoms Alkyl. The alkynyl bond can be unconjugated or shared to another unsaturated group. Suitable alkynyl groups include, but are not limited to, C2_6 alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropanyl, 4-fluorenyl-1.butynyl, 4-propyl-2-pentyl and 4-butyl-2-hexynyl. An alkynyl can be unsubstituted or substituted with one or two suitable substituents. The term "cycloalkyl" is used alone or as a suffix or prefix and refers to a saturated monovalent ring-containing hydrocarbon group containing at least 3 to up to about 12 carbon atoms. Examples of cycloalkyl include, but are not limited to, C: 3.7 cycloalkyl, such as cyclopropyl, cyclobutyl, 101539 200539856 cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes class. A cycloalkyl can be unsubstituted or substituted with one or two suitable substituents. The cycloalkyl group is preferably a monocyclic ring or a bicyclic ring. The term "cycloalkenyl", used alone or as a suffix or prefix, refers to a monovalent cyclic hydrocarbon group having at least one carbon-carbon double bond and containing at least 3 to up to about 12 carbon atoms. Alkynyl " Division, used alone or as a suffix or prefix, means having

至少一個碳·碳參鍵，且包含約7個至高達約12個碳原子之 含單價環烴基。 芳基周，單獨或作為字尾或字首使用，係指單價烴 基，具有-或多個具有芳族特性（例如4n+2個去定域化電 子:：多，飽和碳環，且包含5個至高達約14個碳原子。 、— 词單獨或作為字尾或字首使用，係指二價 煙基，具有—或多個具有芳族特性（例如4η + 2個去定域化 之多不飽和碳環，且包含5個至高達約Μ個碳原子， 八係用以使兩種結構連結在一起。 構=二有單獨或作為字尾或字首使用，係指含環結 原子作為環結L— 子在環中。雜产可立^ L 3至少3個而至高約20個原 且雜環可含有=為飽和或不飽和，含有—或多個雙鍵， 時，玆严 以上之環。當雜環含有一個以上之環 環，共用其間之兩二;：稍合環一般係指至㈣ 有芳族特性。自原子。雜核可具有芳族特性或可不具 101539 200539856 社谨雜/八無’―詞’單獨或作為字尾或字首使用，係指人π 、’° "刀子’具有-或多個獨立選自Ν、〇、!>及8 :: 雜原子作為環結構 夕饧 個原子在環中，：二 含至少3個而至高約20 4,去定域化電I3環結構或分子具有芳族特性(例如A monovalent cyclic hydrocarbon group containing at least one carbon · carbon reference bond and containing about 7 to up to about 12 carbon atoms. Aryl week, used alone or as a suffix or prefix, refers to a monovalent hydrocarbon group with-or more aromatic properties (eg, 4n + 2 delocalized electrons :: poly, saturated carbocyclic, and contains 5 Up to about 14 carbon atoms., — The word is used alone or as a suffix or prefix, referring to a divalent nicotinic group, having — or more aromatic properties (such as 4η + 2 delocalized as many Unsaturated carbocyclic rings, containing 5 to up to about M carbon atoms, eight systems are used to link two structures together. Structure = two have separate or used as a suffix or prefix, refers to a ring-containing atom as The ring junction L— the son is in the ring. The heterogeneity may be at least 3 and up to about 20 atoms. The heterocyclic ring may contain = is saturated or unsaturated and contains-or more double bonds. The ring. When the heterocyclic ring contains more than one ring ring, the two in between are shared ;: A slightly closed ring generally refers to ㈣ has aromatic properties. Self-atoms. The heteronucleus may have aromatic properties or may not have 101539 200539856. Miscellaneous / Ba Wu '-the word' single or used as a suffix or prefix, referring to people π, '° " 刀' ' -Or more independently selected from N, 〇,! ≫ and 8 :: heteroatom as ring structure, with one atom in the ring: two containing at least 3 and up to about 20 4, delocalized electric I3 ring Structure or molecule has aromatic properties (e.g.

㈣A作為子尾或子I使用，係 除-或多個氫所衍生之基圏。 從雜％移 ,雜環基”-詞’單獨或作為字尾或字首使用，係 從雜環移除一個氫所衍生之單價基團。 由L次雜雜環基，，—詞，單獨或作為字尾或字首使用，係指藉 由攸雜環移除兩個氫所衍生之二價基團，其係用以使兩種 結構連結在一起。 "六員"一詞，作為字首使用，係指具有含有六個環原子 之環之基團。 "五員”一言g，作為字首使用’❹具有含有五個環原子 之環之基團。 五員％雜芳基為具有環之雜芳基，該環具有五個環原子， 其中1、2或3個環原子係獨立選自N、〇及s。 舉例之五員環雜芳基為嘧吩基、呋喃基、吡咯基、咪唑 基、p塞唾基、巧唾基、峨。坐基、異遠嗤基 '異巧σ坐基、1，2 3· —唑基、四唑基' 1，2,3-噻二唑基' 1，2,3-4二唑基、丨，2,4·三唑 基、1，2,4_嘧二唑基、1，2,4_崎二唑基、ι，3,4-三唑基、丨，“‘二 唾基及1，3,4-今二嗤基。 101539 -10- 200539856 六員環雜芳基為具有環之雜芳基， 甘rb 1 1^衣具有六個環原早， 其中1，2或3個環原子係獨立選自N、〇及s。 子 舉例之六員環雜芳基為吡啶基、+ 甘” W开基、嘧啶基、=咕 基及嗒畊基。 一开 係指具有 雜方基"一詞，單獨或作為字尾或字首使用 芳族特性之雜環基。㈣A is used as a sub-tail or sub-I, and is a radical derived from-or more hydrogen. Shift from hetero%, heterocyclyl "-the word 'alone or used as a suffix or prefix, is a monovalent group derived from the removal of a hydrogen from a heterocycle. Heterocyclic heterocyclyl by L times ,,-word, alone Or used as a suffix or prefix, refers to the divalent group derived by removing two hydrogens through a heterocyclic ring, which is used to link the two structures together. &Quot; 六 member ", Used as a prefix refers to a group having a ring containing six ring atoms. &Quot; Five members " a word g, as a prefix, '❹ has a group containing a ring containing five ring atoms. The 5-membered heteroaryl group is a heteroaryl group having a ring having five ring atoms, of which 1, 2 or 3 ring atoms are independently selected from N, 0 and s. Examples of five-membered heterocyclic aryl groups are pyrenyl, furyl, pyrrolyl, imidazolyl, p-sialyl, sialyl, and fluorene. Sorryl, isodistoryl, 'heterosigma stilbyl, 1, 2 3-—azolyl, tetrazolyl' 1,2,3-thiadiazolyl '1,2,3-4 diazolyl, 丨, 2,4 · triazolyl, 1,2,4_pyrimidazolyl, 1,2,4_azodiazolyl, ι, 3,4-triazolyl, 丨 "'disialyl and 1 , 3,4-present difluorenyl group. 101539 -10- 200539856 Six-membered ring heteroaryl is a heteroaryl group having a ring, and rb 1 1 ^ coat has six ring original groups, of which 1, 2, or 3 rings The atomic system is independently selected from N, 0, and s. Examples of six-membered ring heteroaryl groups are pyridyl, + glycanyl, pyrimidinyl, pyridyl, and daphthyl. One open refers to a heterocyclic group having the term "heterosquares", used alone or as a suffix or prefix, with aromatic properties.

/，雜環㈣"―詞，單獨或作為字尾或字首使用，係指單 J衣狀或多環狀環’包含碳與氫原子，及至少一個雜原子， 較佳為⑴個選自氣、氧及硫之雜原子，且未具有不飽和 性。雜環烧基之實例包括四氫㈣基、四氫㈣基、六氣 峨咬基、六氫㈣基、六氫t井基、六氫㈣基、嗎心林 基、嗎福啉基、硫代嗎福啉基、硫代嗎福啉基及哌喃基。 雜環烷基可為未經取代，或被一或兩個適當取代基取代。 雜環烷基較佳為單環狀或雙環狀環，更佳為單環狀環，其 中該環包含3至6個碳原子及1至3個雜原子，於本文中稱為 C3 - 6雜環烧基。 雜環包括例如單環狀雜環，譬如：氮丙啶、環氧乙烷、 環硫乙烧、一氮四圜、環氧丙烧、環硫丙烧、四氫p比洛、 二氫峨17各、四氫咪嗤、四氫峨嗤、二氫ϊτ比嗤、二氧伍圜、 環丁颯、2,3-二氫呋喃、2,5-二氫呋喃、四氫呋喃、嘍吩烷、 六氫峨σ定、1，2,3,6-四氫·峨σ定、六氫ρ比畊、嗎福琳、硫代嗎 福啉、哌喃、硫代哌喃、2,3-二氫哌喃、四氫哌喃、1，4-二氫 叶匕σ定、1，4-二氧陸圜、1，3_二氧陸圜、二氧陸圜、高六氫？比咬、 2,3,4,7-四氫-1Η —氮七圜烯、高六氫吡畊、1,3-二氧七圜、4,7- 101539 -11 - 200539856 二氫-1，3-二氧氮七圜烯及環氧己烷。 此外，雜環包括芳族雜環，例如咐咬、々 ㈠吩、，南、吱咕、…咪唾、喧唾…坐”、塔 U，3-二唑、四唑、1>2,3_屢二唑 口坐、1，2,4-三哇、U4_喧二唑、1 2 ，2,3-气二 嘧二唑及1，3,4-呤二唑。 Λ U，4·三啥、1，3,4- 另外’雜環涵蓋多環狀雜環，例如啊、_ 仲林、喳啉、四氫 -外朵、異 一窗味圄夭 ，、啥林、四氧異口奎淋、14笼丘 一巩陸園、香豆素、二氯香豆素、笨 认本开 ㈣、異苯并吱喃”克稀、咬、異咬、黃^辛、氧笨并 陸圜烯、噻蒽、吲g 7素、本氧硫 1井異唾、嗓呤、吹咕, 喹哼啉、喹唑啉、嗉 开、嗉啶、 怀哞啉、喋啶、菲啶、呕啶一 命、紛㈣m⑽并異啊、料❹=、、/非 峻、苯并p塞哇、芏丑 力 本并吟 本开咪唑、苯并三唑、硫基黃嘌‘、 ㈣H ^各里西<及4諾里西σ定。 k ' 除了上述多環狀雜環以 在兩個或多個環間之…二括夕％狀雜環，其中 鍵结，盥赶、… ’。過一個對兩環共用之 ==超過兩個對兩環共用之原子。 實例包括奎寧璟、_ — _ 们伐濰％之 庚烷。 又—鼠雙環并[2·2·1]庚烷及7-氧雙環并[2.2J] 雜％基包括例如單環狀雜環基，譬如 乙炫基、環硫乙" 见内疋I %乳 p其 卜 疋土、一虱四圜基、環氧丙烷基、環硫丙 ._. u —虱吡咯基、四氫咪唑基、四氫吡唑 暴、一風P比唾基、-$ —虱伍圜基、環丁颯基、2,3_二氫呋喃基、 101539 -12- 200539856 2,5-二氫呋喃基、四氫呋喃基、喳吩烷基、六氫吡啶基、^2,3,6-四氫4比啶基、六氫吡畊基、嗎福淋基、硫代嗎福琳基、旅 — 喃基、硫代喊喃基、2,3-二氫哌喃基、四氫略喃基、1，4-二氫 • 吡啶基、1，4-二氧陸圜基、1，3-二氧陸圜基、二氧陸圜基、高 六氫吡啶基、2,3,4,7_四氫·1Η-—氮七圜烯基、高六氫吡畊基、 1，3-二氧七圜基、4,7-二氫·1，3-二氧氮七圜烯基及六亞甲基氧 化基。 ^ 此外，雜環基包括芳族雜環基或雜芳基，例如吡啶基、 吡畊基、嘧啶基、嗒畊基、噻吩基、呋喃基、呋咕基、吡 咯基、咪唑基、嘧唑基、嘮唑基、吡唑基、異嘧唑基、異 崎唑基、1，2,3-三峻基、四唑基、1，2,3-遠二吐基、1，2,3-巧二嗤 基、1，2,4-三唑基、1，2,4-遠二唑基、1，2，扣号二唑基、ι，3,4-三嗤 基、1，3,4-ρ塞二σ坐基及1，3,4$二嗤基。 另外，雜環基涵蓋多環狀雜環基（包括芳族或非芳族兩 者），例如啕哚基、二氫吲哚基、異吲哚啉基、喹啉基、四 φ 氫喹啉基、異喹啉基、四氫異喳啉基、1，4-苯并二氧陸圜基、 香豆基、二氫香豆基、苯并呋喃基、2,3_二氫苯并呋喃基、 異苯并呋喃基、咣烯基、咣基、異咣基、咄基、苯氧硫陸 圜烯基、嘍嗯基、吲畊基、異吲哚基、峭唑基、嘌呤基、 ， σ太畊基、哈σ定基、峻喏琳基、0奎唾琳基、唓淋基、嗓Π定基、 •啡啶基、呕啶基、啡啉基、啡畊基、啡嘧畊基、啡嘮畊基、 1,2-本并異巧u坐基、笨并硫苯基、苯并，号α坐基、苯并ρ塞唾基、 苯并咪唑基、苯并三唑基、硫基黃嘌呤基、咔唑基、咔啉 基、吖啶基、吡咯里西啶基及喹諾里西啶基。/, Heterocyclic ring "-word, used alone or as a suffix or prefix, refers to a single J-like or polycyclic ring 'containing carbon and hydrogen atoms, and at least one heteroatom, preferably one selected from Heteroatoms of gas, oxygen and sulfur, and not unsaturated. Examples of heterocyclic alkyl groups include tetrahydrofluorenyl, tetrahydrofluorenyl, hexahydrofluorenyl, hexahydrofluorenyl, hexahydrotyl, hexahydrofluorenyl, morpholinyl, morpholinyl, sulfur Substituted morpholinyl, thiomorpholinyl and piperanyl. Heterocycloalkyl can be unsubstituted or substituted with one or two suitable substituents. Heterocycloalkyl is preferably a monocyclic or bicyclic ring, more preferably a monocyclic ring, wherein the ring contains 3 to 6 carbon atoms and 1 to 3 heteroatoms, and is referred to herein as C3-6 Heterocycloalkyl. Heterocyclics include, for example, monocyclic heterocyclic rings, such as: aziridine, ethylene oxide, epithiine, monoazatetramethylene, propylene oxide, epithiine, tetrahydropilo, dihydropyridine 17 each, Tetrahydroimidine, Tetrahydropyridine, Dihydropyridine, Bioxane, Dioxolane, Cyclopentamidine, 2,3-Dihydrofuran, 2,5-Dihydrofuran, Tetrahydrofuran, Benzene, Hexahydroeigidine, 1,2,3,6-tetrahydro · eosigidine, hexahydro-pigment, morpholin, thiomorpholine, piperan, thiopiperan, 2,3-di Hydropiperan, tetrahydropiperan, 1,4-dihydropyridine, 1,4-dioxolane, 1,3-dioxolane, dioxolane, homohexahydro? Specific bite, 2,3,4,7-tetrahydro-1Η-azaheptaene, homohexahydropyridine, 1,3-dioxetane, 4,7- 101539 -11-200539856 dihydro-1, 3-dioxazepinene and hexane. In addition, heterocycles include aromatic heterocycles, such as succinct, succinyl, sulphur, squeak, ... misal, noisy ... sit ", U, 3-diazole, tetrazole, 1 > 2,3 _Zodiazol, 1,2,4-tri-Wa, U4_Xandiazole, 1 2, 2,3-Pyrimidiazole and 1,3,4-Puridiazole. Λ U ， 4 · Sansha, 1,3,4- In addition, 'heterocycle' encompasses polycyclic heterocycles, such as ah, _ Zhonglin, perylene, tetrahydro-waiduo, Yiyi window miso, Hanlin, tetraoxo Kui Lin, 14 Cangqiu-Gongluyuan, Coumarin, Dichlorocoumarin, Stupid Open Book, Isobenzocran ", thin, bite, different bite, Astragalus, Oxybenzene and Lupinene, Thianthracene, Ing 7, Benzothiol 1 Isosa, Sophora, Chrysanthemum, Quinaline, Quinazoline, Phenanthrene, Pyridoxine, Pyridoxine, Pyridoxine, Phenanthridine, Vomitidine ㈣, ⑽, ⑽, 异, 异, ❹, /, 非, 峻, 苯, 塞, 塞 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, From, To Benzyl Triazole. And 4 Norris σ. In addition to the above-mentioned polycyclic heterocyclic ring, there are two or more ring-shaped heterocyclic rings between two or more rings, in which bonding, ripping, ... '. Passing one pair of two rings == More than two atoms common to two rings. Examples include quinine tincture, pentamidine, heptane. Also—murine bicyclo [2 · 2 · 1] heptane and 7-oxobicyclo [2.2J] Hetero% groups include, for example, monocyclic heterocyclic groups, such as ethenyl, epithionyl " % Milk p, its soil, mono-tetramethyl, propylene oxide, epithizone. _. U --- pyrrolyl, tetrahydroimidazolyl, tetrahydropyrazol, Yifeng P than salyl,- $ --- carbofluorenyl, cyclobutyryl, 2,3-dihydrofuryl, 101539 -12- 200539856 2,5-dihydrofuryl, tetrahydrofuryl, fluorenylalkyl, hexahydropyridyl, ^ 2,3 , 6-tetrahydro4-pyridyl, hexahydropyridyl, morpholinyl, thiomorpholinyl, bris-yl, thiocarbamyl, 2,3-dihydropiperanyl, tetra Hydrolylyl, 1,4-dihydropyridyl, 1,4-dioxolyl, 1,3-dioxolyl, dioxolyl, homohexahydropyridyl, 2,3 , 4,7_tetrahydro · 1Η-azaheptaenyl, homohexahydropyridyl, 1,3-dioxafluorenyl, 4,7-dihydro · 1,3-dioxazepine Alkenyl and hexamethylene oxide. ^ In addition, heterocyclic groups include aromatic heterocyclic groups or heteroaryl groups, such as pyridyl, pyridyl, pyrimidinyl, daphnyl, thienyl, furyl, furyl, pyrrolyl, imidazolyl, pyrazole Base, oxazolyl, pyrazolyl, isopyrazolyl, isozazolyl, 1,2,3-trisyl, tetrazolyl, 1,2,3-tetradoxyl, 1,2,3 -Carbodifluorenyl, 1,2,4-triazolyl, 1,2,4-tetradiazolyl, 1,2, oxadiazolyl, ι, 3,4-trifluorenyl, 1, 3 , 4-ρ plug diσ base and 1,3,4 $ difluorenyl base. In addition, heterocyclyl encompasses polycyclic heterocyclic groups (both aromatic and non-aromatic), such as fluorinyl, dihydroindolyl, isoindolinyl, quinolinyl, and tetra-phi hydroquinoline Base, isoquinolinyl, tetrahydroisofluorinyl, 1,4-benzodioxoyl, coumaryl, dihydrocoumaryl, benzofuranyl, 2,3-dihydrobenzofuran Group, isobenzofuranyl, pinenyl, fluorenyl, isofluorenyl, fluorenyl, phenoxythioarmenenyl, fluorenyl, indyl, isoindolyl, amidazolyl, purine, , Σ Taikenji, Ha σdingji, Junyilinji, 0 Kuisalinyl, Glyphosphyl, Houyiji, • Pyrimidinyl, chloridinyl, morpholinyl, morpholinyl, morpholinyl , Phenanthrene, 1,2-benzyl, benzothio, benzothiophenyl, benzo, alpha, benzothiazyl, benzimidazolyl, benzotriazolyl, Thioxanyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolidsinyl.

lOIS^Q 200539856 除了上述多環狀雜環基以& 土 Μ外’雜環基包含多環狀雜環基， 其中在兩個或多個環間之瑗翻人 ^ 衣稠合，包含超過一個對兩環共 用之鍵結’與超過兩個對兩環共用之原子。此種經橋接雜 環之實例，包括奎寧環基、二氮雙環并[22.基及7_氧雙 環并[2.2.1]庚基。lOIS ^ Q 200539856 In addition to the above-mentioned polycyclic heterocyclic groups, the heterocyclic group contains a polycyclic heterocyclic group, in which the ring between two or more rings is fused and contains more than A bond shared by one pair of rings and an atom shared by more than two pairs of rings. Examples of such bridged heterocyclic rings include quinuclidinyl, diazabicyclo [22.yl, and 7-oxobicyclo [2.2.1] heptyl.

’’烧氧基”-詞，單獨或作為字尾或字首使用，係指通式 -0-R基團，其中R係選自烴基。舉例之烧氧基包括甲氧基、 乙氧基、丙氧基、異丙氧基、丁氧基、第三—丁氧基、異丁 氧基、環丙基甲氧基、烯丙氧基及炔丙基氧基。 π胺π或"胺基"術語係HNh2。 鹵素包括氟、氣、溴及碘。 π鹵化”作為基團之字首使用，係意謂在基團上之一或多 個氫被一或多個鹵素置換。 ’’RTn、"r.t."或”rt”係意謂室溫。 DMF係指二甲基甲醯胺。 ’’DIPEA”係指N，N-二異丙基乙胺。 ΙΉΑΤυ”係指六氟磷酸2-(7-氮苯并三唑-1-基）-1，1，3,3-四甲 基錁。 本發明之—方面為式I化合物，其藥學上可接受之鹽，其 非對映異構物、對掌異構物或混合物： 〇 ’、'' Axyloxy ''-word, used alone or as a suffix or prefix, refers to a group of the general formula -0-R, where R is selected from a hydrocarbon group. Examples of alkoxy include methoxy and ethoxy , Propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy and propargyloxy. Πamineπ or " The term "amino" refers to HNh2. Halogen includes fluorine, gas, bromine and iodine. "Pi halogenation" is used as the prefix of a group, meaning that one or more hydrogens on the group are replaced by one or more halogens. '’RTn, " r.t. " or" rt "means room temperature. DMF means dimethylformamide. "DIPEA" means N, N-diisopropylethylamine. ΙΑΑΤυ "means 2- (7-nitrobenzotriazol-1-yl) -1,1,3,3-tetramethylhexafluorophosphate Base One aspect of the present invention is a compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, a para-isomer or a mixture thereof:

/(CH2)n-R4/ (CH2) n-R4

N \ ^N \ ^

101539 -14- 200539856 其中： m係選自0, 1及2 ; n係選自0, 1，2,3,4及5 ; R1係獨立選自！I素、氰基、胺基、硝基、C16烷胺基、 二Ci·6烷胺基、乙醯胺基、羥基、。^烷氧基、6烷基、 鹵化C^6烷氧基、Cl-6烯基及鹵化Ci6烷基； ' R2係選自（：6·1〇芳基與（：2-1〇雜環基；其中該用於定義R2之 I i〇芳基與C2_〗〇雜環基係視情況被一或多個基團取代，該 基團係選自_素、幽化C1_6烷基、c1-6烷基、氰基、硝基、 Cl-6烧氧基、鹵化(^_6烷氧基、羥基、羥基_Cl 6烷基、胺基、 Ci-6烷氧基-Ci-6烷基、Cle6烷羰基、Ci-6烷氧羰基、Ci-6烷 胺基、二Cu烷基-胺基、胺基-Ci6烷基、c36環烷基、c2-6 雜芳基、雜芳基-Ch烷基、c6-10芳基及c6-10芳基-Ci-6烷 基；且 R3係選自氫與C!-6烷基；R4係選自c1-6烷基、c37環烷 φ 基、C4-7環烯基、C6-i〇芳基、C2-6雜環基-胺基、c2-6雜環基 氧基-胺基及(：2_6雜環基；其中該用於定義圮之Ci6烷基、 C3_7環烧基、C4_7環烯基、c6-10芳基、C2-6雜環基-胺基、 C2 -6雜環基氧基-胺基及C2 - 6雜環基，係視情況被一或多個 基團取代，該基團係選自_素、鹵化Cil烷基、Cij烷基、 氰基、硝基、烷氧基、鹵化cl-6烷氧基、羥基、羥基-Ci-6 烧基、胺基 Cl - 6烧氧基· 6烧基、Ci-6烧魏基、Ci-6烧氧 爹厌基、Cl - 6烧fee基、>一 C! _ 6烧基胺基、胺基-C卜6烧基、C3 - 6 玉衣烧基、C〗_6雜方基、雜方基-Cl _6烧基、C。10芳基及C6-10 101539 •15- 200539856 (CH2)-R4 芳基烷基 係為C2 - 1 0雜環基 其係視 情況被一或多個基團取代，該團基係選自_素、經_素取 代之Ci _6烧基、c1-6烧基、氰基、頌基、（^-6烧氧基、鹵化101539 -14- 200539856 where: m is selected from 0, 1 and 2; n is selected from 0, 1, 2, 3, 4 and 5; R1 is independently selected from! I element, cyano group, amine group, nitro group, C16 alkylamino group, diCi-6 alkylamino group, acetamido group, hydroxyl group, etc. ^ Alkoxy, 6 alkyl, halogenated C ^ 6 alkoxy, Cl-6 alkenyl, and halogenated Ci6 alkyl; 'R2 is selected from (: 6.10 aryl and (: 2-10 heterocycles) Wherein the I i〇aryl group and C2_ 〖heterocyclic group used to define R2 are optionally substituted by one or more groups, the group is selected from the group consisting of _ prime, C1_6 alkyl, c1- 6 alkyl, cyano, nitro, Cl-6 alkoxy, halogenated (^ -6 alkoxy, hydroxyl, hydroxy_Cl 6 alkyl, amino, Ci-6 alkoxy-Ci-6 alkyl, Cle6 alkylcarbonyl, Ci-6 alkoxycarbonyl, Ci-6 alkylamino, diCualkyl-amino, amino-Ci6 alkyl, c36 cycloalkyl, c2-6 heteroaryl, heteroaryl-Ch Alkyl, c6-10 aryl, and c6-10 aryl-Ci-6 alkyl; and R3 is selected from hydrogen and C! -6 alkyl; R4 is selected from c1-6 alkyl and c37 naphthenic φ groups , C4-7 cycloalkenyl, C6-io aryl, C2-6 heterocyclyl-amino, c2-6 heterocyclyloxy-amino, and (: 2-6 heterocyclyl; where this is used to define 圮Ci6 alkyl, C3_7 cycloalkenyl, C4_7 cycloalkenyl, c6-10 aryl, C2-6 heterocyclyl-amino, C2-6 heterocyclyloxy-amino, and C2-6 heterocyclyl, Optionally substituted by one or more groups Self-priming, halogenated Cil alkyl, Cij alkyl, cyano, nitro, alkoxy, halogenated cl-6 alkoxy, hydroxyl, hydroxyl-Ci-6 alkyl, amine Cl-6 alkyl, 6-Alkyl, Ci-6-Alkyl, Ci-6-Alkyl, Cl-6, A-Fee, > -C! _ 6-Alkylamino, Amine-C, 6-Alkyl, C3- 6 Yuyi sintering group, C〗 _6 heterosquaryl, heterosquaryl-Cl _ 6singular, C. 10 aryl and C6-10 101539 • 15- 200539856 (CH2) -R4 arylalkyl system is C2-1 0 Heterocyclyl is optionally substituted by one or more groups, the group is selected from the group consisting of Ci-6, Ci-6 alkyl, c1-6 alkyl, cyano, sulfonyl, (^ -6 burned oxygen, halogenated

Cu烷氧基、羥基、羥基-Ci-6烷基、胺基、Cu烷氧基-Ch 烧基、（V6烷羰基、Ci_6烷氧羰基、Cm烷胺基、二烷 基-胺基、胺基-q-6烷基、（：3-6環烷基、C2-6雜芳基、雜芳 基-Ci _6烧基、C6_10芳基及Cg-io芳基-Ci - 6院基。Cu alkoxy, hydroxyl, hydroxy-Ci-6 alkyl, amine, Cu alkoxy-Ch alkyl, (V6 alkylcarbonyl, Ci-6 alkoxycarbonyl, Cm alkylamino, dialkyl-amine, amine -Q-6 alkyl, (3-6 cycloalkyl, C2-6 heteroaryl, heteroaryl-Ci-6 alkyl, C6-10 aryl and Cg-ioaryl-Ci-6 alkyl.

於另一項具體實施例中，本發明化合物係為式I化合物， 其中 m係選自〇, 1及2 ; η係選自〇，1，2,3及4; R1係獨立選自_素、氰基、胺基、硝基、乙醯胺基、羥 基、Q-3烧氧基、Ci_3烷基、鹵化Ci 3烷氧基及_化(：卜^烷 基； R2係選自cn〇芳基與C2-10雜環基，其中該用於定義R2之 C6-10芳基與C2_io雜環基，係視情況被一或多個基團取代， 該基團係選自鹵素、鹵化Ci-3烷基、Ci-3烷基、硝基、Ad 烧氧基、鹵化ci·3烧氧基、羥基、經基-CV3烧基、胺基、 Cu烧氧基-Ci_3烷基、C2 5雜環基-Ci 3烷基、6烷氧羰 基、CH燒胺基、二Ch烷基-胺基及胺基 <卜3烷基；且 R3係選自氫與Cl·6烷基；R4係選自Ci_6烷基、c3_7環烷 基、C2·6雜環基-胺基、C：2·6雜環基氧基·胺基及(^6雜環基； 其中該用於定義R4之Cl_6烷基、C37環烷基、C26雜環基_ 101539 -16· 200539856 胺基、C2-6雜環基氧基-胺基及C2-6雜環基’視情況被一或 多個基團取代，該基團係選自鹵素、逢化C1-3烷基、Ci-3 烧基、石肖基、Ci - 3烧氧基、鹵化Cl - 3烧氧基、羧基、經基_Ci - 3 烷基、胺基、Ci-3烷氧基-(^-3烷基、（^-6烷氧羰基、Q-3烷 •K，—r4 胺基、二Ci- 3烧基-胺基及胺基-Cl - 3烧基，或 R 係 選自一氮七圜烷基、吡咯基、二氫吡咯基、四氫吡咯基、 咪唾基、四氫咪峻基、卩比嗤基、二氫P比嗤基、四氫峨嗤基、 異四氫4σ坐基、三唆基、嗎福淋基、六氫P比咬基、硫代嗎 福啉基、嗒畊基、六氫吡畊基、三畊基或1，4-二氧各氮螺[4.5] 癸各基；其中該一氮七圜烷基、吡咯基、二氫吡咯基、四 氫吡咯基、咪唑基、四氳咪唑基、吡唑基、二氫吡唑基、 四氫卩比嗤基、異四氫吟β坐基、三n坐基、嗎福琳基、六氫口比 °定基、硫代嗎福啉基、六氫吡畊基、三啡基及丨，孓二氧各氮 螺[4.5]癸-8-基，係視情況被一或多個基團取代，該基團係選 自鹵素、_化^」烷基、（：卜3烷基、硝基、（：卜3烷氧基、鹵 化心·3烷氧基、羥基、羥基七㈠烷基、胺基、Ci3烷氧基-Ci3 燒基、Cy燒氧羰基、Cl_3烷胺基、二Cl-3烷基-胺基及胺基 •Cl - 3燒基。 於進一步具體實施例中，本發明化合物係為式I化合物， 其中 m係選自0與i ; n係選自0, 1，2,3及4 ; 尺係獨立選自i素、胺基、硝基、乙酿胺基、經基、q - 3 101539 -17- 200539856 烧氧基、Cm院基、鹵化Ci-3烧氧基及_化(^-3烧基； R2係選自苯基、莕基、吡啶基、吡畊基、嘧啶基、嗒畊 基、違吩基、吱喃基、峨洛基、α米嗤基、遠嗤基、崎嗤基、 吡唑基、異嘧唑基、異嘮唑基、1，2,3-三唑基、四唑基、1，2,3- 噻二唑基、1，2,3-噚二唑基、1，2,4_三唑基、1，2,4_禮二唑基、1，2,4- 呤二唑基、1，3,4-三唑基、1，3,4_噻二唑基及1，3,4呤二唑基、吲 哚基、二氫吲哚基、喹啉基、四氫喹啉基、異喹啉基、四 氫異喳啉基、1，4-苯并二氧陸圜基、香豆素、二氫香豆基、 2,3-二氫苯并呋喃基、1，2·苯并異嘮唑基、l，3-苯并二氧伍圜 烯基、2,3·二氫-1，4-苯并二氧陸圜烯基、3,4-二氫-2Η-1，5_苯并 二氧氮七圜烯基、4Η-1，3-苯并二氧陸圜烯基、苯并呋喃基、 苯并硫苯基、苯并嘮唑基、苯并喳唑基、苯并咪唑基、苯 并三唾基、硫基黃嘌呤基、咔唑基、咔啉基、吖啶基、吡 咯里西啶基及喹諾里西啶基，其係視情況被一或多個基團 取代，該基團係選自！|素、羥基、甲基、甲氧基、胺基、 三氣甲基、三敦甲氧基、甲氧基甲基、1Η-1，2,3-三唑基甲基 及1Η-吡唑基甲基； R3係選自氫與Cl_6烷基；且 R4係選自 101539 -18- 200539856In another specific embodiment, the compound of the present invention is a compound of formula I, wherein m is selected from the group consisting of 0, 1 and 2; η is selected from the group consisting of 0, 1, 2, 3 and 4; R1 is independently selected from the group consisting of , Cyano, amine, nitro, acetamido, hydroxy, Q-3 alkoxy, Ci_3 alkyl, halogenated Ci 3 alkoxy, and R () alkyl; R2 is selected from cn. An aryl group and a C2-10 heterocyclic group, wherein the C6-10 aryl group and C2_io heterocyclic group used to define R2 are optionally substituted by one or more groups, and the group is selected from halogen, halogenated Ci -3 alkyl group, Ci-3 alkyl group, nitro group, Ad alkoxy group, halogenated ci · 3 alkoxy group, hydroxyl group, via group-CV3 alkoxy group, amine group, Cu alkoxy group-Ci_3 alkyl group, C2 5 Heterocyclyl-Ci 3 alkyl, 6 alkoxycarbonyl, CH alkyl, di-Ch alkyl-amino and amine <alkyl; R 3 is selected from hydrogen and Cl 6 alkyl; R 4 Is selected from Ci_6 alkyl, c3_7 cycloalkyl, C2 · 6 heterocyclyl-amino, C: 2 · 6 heterocyclyloxy · amino, and (^ 6 heterocyclyl; where this is used to define R4 Cl_6 alkyl, C37 cycloalkyl, C26 heterocyclyl_ 101539 -16 · 200539856 Amine, C2-6 heterocyclyloxy-amino and C2-6 heterocyclyl 'as appropriate Substituted by one or more groups selected from the group consisting of halogen, C1-3 alkyl, Ci-3 alkyl, Schottky, Ci-3 alkyl, halogenated Cl-3 alkyl, carboxyl, Carbo-Ci-3 alkyl, amine, Ci-3 alkoxy-(^-3 alkyl, (^ -6 alkoxycarbonyl, Q-3 alkane • K, -r4 amine, di Ci-3 Alkyl-amino and amine-Cl-3 alkyl, or R is selected from the group consisting of monoaza heptyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, imidyl, tetrahydroimidyl, Fluorenyl, hydrazyl, dihydropyridinyl, tetrahydropyridyl, isotetrahydro 4σ-phenyl, trisynyl, morpholinyl, hexahydropyridinyl, thiomorpholinyl, daikon Base, hexahydropyracyl, tricrotyl, or 1,4-dioxoazepine [4.5] decyl; wherein the monoaza heptyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, Imidazolyl, tetramethylimidazolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyridyl, isotetrahydropyridyl, trinyl, morpholinyl, hexahydropyridyl, Thiomorpholinyl, hexahydropyridyl, triphinyl, and 孓, dioxoazepine [4.5] dec-8-yl, depending on the situation A plurality of groups are substituted, and the group is selected from the group consisting of halogen, alkyl, alkoxide, nitro, alkoxy, alkoxy, alkoxy, hydroxy, and hydroxy Heptadecyl, amine, Ci3 alkoxy-Ci3 alkyl, Cy alkyloxycarbonyl, Cl_3 alkylamino, diCl-3 alkyl-amino and amine • Cl-3 alkyl. Further specific implementation In the example, the compound of the present invention is a compound of formula I, wherein m is selected from 0 and i; n is selected from 0, 1, 2, 3, and 4; and the ruler is independently selected from i, amine, nitro, and ethyl. Fermented amine, mesogen, q-3 101539 -17- 200539856 alkoxy, Cm radical, halogenated Ci-3 alkoxy, and ^ -3 alkoxy; R2 is selected from phenyl, fluorenyl, Pyridyl, pyrimidinyl, pyrimidinyl, daphnyl, phenanyl, ranyl, eryl, α-methylpyridyl, farbenzyl, rugosyl, pyrazolyl, isopyrazolyl, isopyridyl Oxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 , 2,4_Lidiazolyl, 1,2,4-pyridoxazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4pyridadiazole Base, indolyl, indane Indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisofluorinyl, 1,4-benzodioxolyl, coumarin, dihydrocoumaryl, 2,3 -Dihydrobenzofuranyl, 1,2 · benzoisoxazolyl, 1,3-benzodioxolenyl, 2,3 · dihydro-1,4-benzodioxolene Base, 3,4-dihydro-2fluorene-1,5-benzobenzodiazepinenyl, 4fluorene-1,3-benzodioxolapinenyl, benzofuranyl, benzothiophenyl , Benzoxazolyl, benzoxazolyl, benzimidazolyl, benzotrisialyl, thioxanthyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidine, and quinol Risetidinyl, which is optionally substituted by one or more groups, the group is selected from! | Vin, hydroxy, methyl, methoxy, amine, trimethyl, trimethoxy, methoxymethyl, 1Η-1,2,3-triazolylmethyl and 1Η-pyrazole R3 is selected from hydrogen and Cl_6 alkyl; and R4 is selected from 101539 -18-200539856

四氫吡咯-1-胺基、六氫吡啶小胺基、ο-環己基羥胺基、Ο i哀戍基經胺基、Ο-環丁基羥胺基、〇-環丙基羥胺基及匚卜3Tetrahydropyrrole-1-amino group, hexahydropyridine small amino group, o-cyclohexylhydroxylamino group, oxalylamino group, 0-cyclobutylhydroxylamino group, 0-cyclopropylhydroxylamino group, and triazole 3

烷基，其係視情況被一或多個基團取代，該基團係選自鹵Alkyl, optionally substituted with one or more groups, the group being selected from halogen

素、胺基、胺基甲基、2-胺基乙基、羥基、羥基甲基、甲 基及乙基。 特定言之，R2係選自Amine, amino, aminomethyl, 2-aminoethyl, hydroxyl, hydroxymethyl, methyl and ethyl. In particular, R2 is selected from

101539 -19- 200539856 其係視情況被一或多個基團取代，該基團係選自鹵素、 曱基、甲氧基、羥基、甲氧基曱基、三唑基曱基及 1H-1，2-二唾基甲基。 於又進一步具體實施例中，本發明化合物係為式I化合物 及其藥學上可接受之鹽， 其中m為1 ; η係選自〇，1，2,及3 ; _ R1係獨立選自_素、胺基、硝基、乙醯胺基、羥基、 烷氧基、q — 3烷基、_化〇：1-3烷氧基及鹵化Ci3烷基； R2係選自苯基、莕基、吡啶基、吡畊基、嘧啶基、嗒畊 基、嘍吩基、吱喃基、吡咯基、咪唑基、噻唑基、嘮唑基、 吡唑基、異噻唑基、異嘮唑基、丨，2,3_三唑基 '四唑基、以义 嘧二唑基、1，2,3-嘮二唑基、ι，2,4-三唑基、1，2/U塞二唑基、1，2,4· 嘮二唑基、1，3,4-三唑基、ι，3,4-禮二唑基與i，3,4二唑基、吲 嗓基、二氫吲哚基、喳啉基、四氫喳啉基、異喹啉基、四 鲁 氫異p奎琳基、i，4·苯并二氧陸圜基、香豆素、二氫香豆基、 2,3-二氫苯并呋喃基、ι，2-苯并異嘮唑基、&苯并二氧伍圜 烯基、2,3-二氫-1，4-苯并二氧陸圜稀基、3,4_二氫-2H-1，5-苯并 二氧氮七圜烯基、4H-1，3-苯并二氧陸圜烯基、苯并呋喃基、 苯并硫苯基、苯并呤唑基、苯并嘍唑基、苯并咪唑基、苯 并三唑基、硫基黃嘌呤基、咔唑基、咔啉基、吖啶基、吡 咯里西啶基及喳諾里西啶基，其係視情況被一或多個基團 取代，該基團係選自_素、羥基、甲基、曱氧基、胺基、 三氟曱基、三氟曱氧基、曱氧基曱基、1Η-1，2,3_三唑基甲基、 101539 -20- 200539856 1H-吡唑基甲基；且101539 -19- 200539856 It is optionally substituted by one or more groups selected from the group consisting of halogen, fluorenyl, methoxy, hydroxyl, methoxyfluorenyl, triazolylfluorenyl and 1H-1 , 2-disialylmethyl. In still further specific embodiments, the compound of the present invention is a compound of formula I and a pharmaceutically acceptable salt thereof, wherein m is 1; η is selected from 0, 1, 2, and 3; _R1 is independently selected from _ Element, amine, nitro, acetamido, hydroxyl, alkoxy, q-3 alkyl, alkoxide: 1-3 alkoxy and halogenated Ci3 alkyl; R2 is selected from phenyl and fluorenyl , Pyridyl, pyrimidinyl, pyrimidinyl, daphnyl, pyrenyl, succino, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 2,3_triazolyl'tetrazolyl, simipyrimidazolyl, 1,2,3-fluoradiazolidyl, ι, 2,4-triazolyl, 1,2 / U thiadiazolyl , 1,2,4 · oxadiazolyl, 1,3,4-triazolyl, ι, 3,4-diadizolyl and i, 3,4diazolyl, indyl, indoline Base, fluorenyl, tetrahydrofluorinyl, isoquinolinyl, tetrahydroisopropyl quinolinyl, i, 4 · benzodioxolyl, coumarin, dihydrocoumarinyl, 2, 3-dihydrobenzofuranyl, ι, 2-benzoisoxazolyl, & benzodioxolenyl, 2,3-dihydro-1,4-benzodioxolidine 3,4_two Hydrogen-2H-1,5-benzodioxazepinenyl, 4H-1,3-benzodioxolhenyl, benzofuranyl, benzothiophenyl, benzoxazolyl, Benzoxazolyl, benzimidazolyl, benzotriazolyl, thioxanthyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidyl, and panosiridinyl, which are Optionally substituted by one or more groups selected from the group consisting of hydrogen, hydroxy, methyl, fluorenyloxy, amine, trifluorofluorenyl, trifluorofluorenyloxy, fluorenylfluorenyl, 1Η -1,2,3-triazolylmethyl, 101539 -20-200539856 1H-pyrazolylmethyl; and

一氮七圜烧基、異四氫 六氫卩比唆基、四氫卩比口各 係選自一氮四圜基、 口号唑基、嗎福啉基、六氫吡呼基、 基及1，4-二氧_8_氮螺[4.5]癸_8-基，其係視情況被一或多個基 團取代，該基團係選自鹵素、氰基、硝基、曱基、乙基、 輕基、羥基-甲基、羥基-乙基、胺基-甲基、胺基-乙基、甲 氧基-甲基、甲氧基-苯基、乙氧羰基、第三-丁氧羰基、二 笨基-甲基、嗎福啉基-乙-2-基、六氫吡啶基-甲基及吡啶基。 知 特定言之， 係選自 101539 -21 · 200539856Hexathiocarbamyl, isotetrahydrohexamidine, and tetrahydropyridine are selected from the group consisting of monoazatetramethyl, slogan oxazolyl, morpholinyl, hexahydropyridyl, and 1 , 4-Dioxo-8-azaspiro [4.5] dec-8- group, which is optionally substituted by one or more groups, the group is selected from halogen, cyano, nitro, fluorenyl, ethyl Group, light group, hydroxy-methyl, hydroxy-ethyl, amine-methyl, amine-ethyl, methoxy-methyl, methoxy-phenyl, ethoxycarbonyl, tert-butoxy Carbonyl, dibenzyl-methyl, morpholinyl-ethyl-2-yl, hexahydropyridyl-methyl and pyridyl. In particular, it is selected from 101539 -21 · 200539856

101539 -22- 200539856101539 -22- 200539856

其係視情況被一或多個基團取代，該基團係選自.素、曱 基、甲氧基、羥基、甲氧基甲基、1114,2,3-三唑基甲基及1H_ 吡唑基甲基。It is optionally substituted by one or more groups selected from the group consisting of sulfonyl, fluorenyl, methoxy, hydroxyl, methoxymethyl, 1114,2,3-triazolylmethyl and 1H_ Pyrazolylmethyl.

於-項更特定具體實施例中，r2係選自In a more specific embodiment of-, r2 is selected from

NN

及and

其係 現情況被一或多個基團取代，該基團係選自鹵素、曱基、 甲氧基、經基 '甲氧基曱基、1H-1，2,3-三唑基曱基及1H-吡唑 基曱基。 101539 -23- 200539856 應明瞭的是;當本發明化合物含有一或多個對掌中心時， =發明化合物可以對掌異構物或非對映異構物形式或以外 肖^ °物存在與單離。本發明包括式I化合物之任何可能 、'、、、構4勿#對映異構物、外消旋物或其混合物。本發 明^ 匕合物=光學活性形式可例如藉由外消旋物之對掌性層 析刀離II由從光學活性起始物質合成，或藉由不對稱合 成，以下述程序為基礎製成。 鲁亦應明瞭的是，本發明之某些化合物可以幾何異構物存 在例如烯類之Ε與Ζ異構物。本發明包括式J化合物之任 何幾何異構物。應進一步明瞭的是，本發明係涵蓋式工化合 物之互變異構物。 亦應月瞭的疋，本發明之某些化合物可以溶劑化合，例 士水σ以及未溶劑化合形式存在。應進一步應明瞭的是， 本發明係涵蓋式1化合物之所有此種溶劑化合形式。 在本發明範圍内者，亦為式I化合物之鹽。一般而言，本 _ ’X月化a物之樂學上可接受之鹽，可使用此項技藝中所習 知之枯準耘序獲得，例如經由使足夠鹼性之化合物，例如 烷基胺，與適當酸例如HC1或醋酸反應，而得生理學上可接 父之陰離子。亦可製成相應鹼金屬（譬如鈉、钟或鐘）或驗 至屬（s如#5 )鹽’其方式是將具有適當酸性質子譬如緩 酸或酚之本發明化合物，在含水媒質中，以一當量之鹼2 屬或鹼土金屬氫氧化物或烷氧化物（譬如乙氧化物或甲氧 基化物）或適當鹼性有機胺（譬如膽鹼或葡曱胺）處理，接著 是習用純化技術。 101539 -24- 200539856 於一項具體實施例中，上述式[化合物可被轉化成其藥學 上可接受之鹽或溶劑合物，特別是酸加成鹽，譬如鹽酸鹽、 氫演酸鹽、磷酸鹽、醋酸鹽、反丁烯二酸鹽、順丁稀二酸 鹽、酒石酸鹽、擰檬酸鹽、甲烷磺酸鹽或對_甲苯磺酸鹽。 吾人目前已發現本發明化合物具有作為醫藥之活性，特 別是作為調制劑或配位體，譬如CBl受體之催動劑、部份催 動劑、逆催動劑或拮抗劑。更特定言之，本發明化合物顯 不作為CB!受體催動劑之活性，且可使用於治療，尤其是舒 解各種疼痛症狀，譬如慢性疼痛.、神經病原性疼痛、急性 疼痛、癌症疼痛、因風濕性關節炎所造成之疼痛、偏頭痛、 内臟疼痛等。但是，此清單不應被解釋為無遺漏。此外， 本發明化合物可使用於其中有CBi受體機能障礙存在或牽 連之其他疾病狀態。再者，本發明化合物可用以治療癌症、 夕I〖生硬化、巴金生氏病、亨丁頓氏舞蹈症、阿耳滋海默 氏疾病、焦慮病症、胃腸病症及心血管病症。 本發明之化合物可作為免疫調制劑使用，尤其是用於自 身免疫疾病，譬如關節炎，皮膚移植物、器官移植及類似 手術需求，膠原疾病、各種過敏反應，作為抗腫瘤劑與抗 病毒劑使用。 本發明化合物可使用於其中類大蔴苷受體之變性或機能 障礙存在或牽連該範例之疾病狀態。這可涉及本發明化合 物以同位素方式標識之變型，在診斷技術與成像應用譬如 陽電子發射局部X射線檢法（PET)上之用途。 本發明化合物可用於治療腹瀉、抑鬱、焦慮及壓力相關 101539 -25- 200539856 病症，譬如外傷後壓力病症、恐懼病症、—般性焦慮病症、 社會恐怖症及迷亂性強迫病症，尿失禁、早茂、各種精神 病、咳漱、肺臟水腫，各種胃腸病症，例如便秘，功能性 胃腸病症’譬如刺激性腸徵㈣與功能性彡肖化不良，巴金 生氏病及其他運動神經病症、外傷性腦部傷害、中風、心 收縮梗塞形成後之心保護、脊髓損傷，及藥瘾，包括酒 於驗、類阿片及其他藥物濫用之治療，及交㈣經系統病 症，例如高血壓。It is now replaced by one or more groups selected from the group consisting of halogen, fluorenyl, methoxy, mesityl'methoxyfluorenyl, 1H-1,2,3-triazolylfluorenyl And 1H-pyrazolylfluorenyl. 101539 -23- 200539856 It should be clear that when the compound of the present invention contains one or more palmar centers, the compound of the present invention may exist in the form of palmar or diastereomers or other compounds. from. The invention includes any possible, enantiomeric, racemic, or mixtures of compounds of Formula I. In the present invention, the dagger compound = optically active form can be synthesized from an optically active starting material, for example, by a pair of palm chromatography chromatography of a racemate, or by asymmetric synthesis, based on the following procedure . Lu should also understand that certain compounds of the present invention may exist as geometric isomers such as the E and Z isomers of alkenes. The invention includes any geometric isomer of the compound of formula J. It should be further understood that the present invention encompasses tautomers of the formulated industrial compounds. It should also be noted that certain compounds of the present invention may be solvated, for example, in water sigma and unsolvated forms. It should further be understood that the invention encompasses all such solvated forms of the compound of formula 1. Those within the scope of the present invention are also salts of compounds of formula I. In general, the musically acceptable salt of this _'monthly a 'can be obtained using conventional procedures known in the art, such as by making a sufficiently basic compound, such as an alkylamine, By reacting with an appropriate acid such as HC1 or acetic acid, an anion that is physiologically accessible to the parent is obtained. It can also be made into the corresponding alkali metal (such as sodium, bell or bell) or genus (s such as # 5) salt by the compound of the present invention having appropriate acidic protons such as retarded acid or phenol in an aqueous medium. , Treated with one equivalent of alkali 2 or alkaline earth metal hydroxide or alkoxide (such as ethoxylate or methoxylate) or appropriate basic organic amine (such as choline or glucosamine), followed by customary purification technology. 101539 -24- 200539856 In a specific embodiment, the compound of the above formula [can be converted into a pharmaceutically acceptable salt or solvate thereof, especially an acid addition salt, such as hydrochloride, hydrogenate, Phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluenesulfonate. We have now found that the compounds of the present invention have pharmaceutical activity, especially as modulators or ligands, such as activators, partial activators, reverse activators or antagonists of the CBl receptor. More specifically, the compounds of the present invention show no activity as CB! Receptor activators, and can be used for treatment, especially to relieve various pain symptoms, such as chronic pain., Neuropathic pain, acute pain, cancer pain, Pain caused by rheumatoid arthritis, migraine, visceral pain, etc. However, this list should not be interpreted as an omission. In addition, the compounds of the invention are useful in other disease states in which CBi receptor dysfunction is present or implicated. Furthermore, the compounds of the present invention can be used to treat cancer, sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders. The compounds of the present invention can be used as immunomodulating agents, especially for autoimmune diseases such as arthritis, skin grafts, organ transplants and similar surgical needs, collagen diseases, various allergic reactions, and as antitumor agents and antiviral agents. . The compounds of the present invention are useful in disease states where degeneration or dysfunction of the cannabinoid receptor is present or implicated in this paradigm. This may involve the use of isotopically labeled variants of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission local X-ray inspection (PET). The compounds of the present invention can be used to treat diarrhea, depression, anxiety, and stress-related conditions, such as 101539 -25-200539856, such as post-traumatic stress disorders, fear disorders, general anxiety disorders, social phobia, and compulsive disorder, urinary incontinence, early Mao, various psychiatric disorders, cough, lung edema, various gastrointestinal disorders, such as constipation, functional gastrointestinal disorders, such as irritating bowel signs and functional dysfunction, Parkinson's disease and other motor neurological disorders, traumatic brain Internal injury, stroke, heart protection after systolic infarction, spinal cord injury, and drug addiction, including alcohol therapy, opioid and other drug abuse treatment, and diseases of the intercourse system, such as hypertension.

本發明化合物可作為止痛劑使用，以在一般麻醉與監控 麻醉護理期間利用。具有不同性質之藥劑之組合，經常用 以達成為保持麻醉狀態所需要作用之平衡（例如記憶缺 失、止痛、肌肉鬆弛及鎮靜作用）。被包含在此組合之中者 二為入麻®r劑、女眠藥、解焦慮劑、神經肌肉阻斷劑及 類阿片。 發明之另一方面係為根據式〗之化合物供抑制短暫 φ 下艮&括、、、勺肌鬆弛（TLESR)，且因此供治療或預防胃與食管 回流病症（GERD)之用途。在回流背後之主要機制已被視為 係依低張f生下食官括約肌而定。但是，例如Hollow# & D⑼t (1990) Gastr0enter〇i_ ain N Amer 19,第 517·535 頁已証實大部份 回",L偶發事件係發生在短暫下食管括約肌鬆弛（TLESR)期 間w即氣、弛並非因吞服而觸發。在進一步具體實施例中， 根據本發明之化合物可用於預防回流、治療或預防反胃、 /α療或預防氣喘、治療或預防喉炎、治療或預防肺病及處 理未能發育健旺。 101539 • 26 - 200539856 本發明之進一步方面係為根據式i化合物於藥劑製造上 之用途，該藥劑係用於抑制短暫下食管括約肌鬆弛，供治 療或預防GERD、預防回流、治療或預防反胃、治療或預防 氣喘、治療或預防喉炎、治療或預防肺病及處理未能發育 健旺。 本發明之又進一步方面係為根據式I化合物於藥劑製造 上之用途，該藥劑係用於治療或預防功能性胃腸病症，譬 如功能性消化不良（FD)。本發明之又再另一方面係為根據 式I化合物於藥劑製造上之用途，該藥劑係用於治療或預防 刺激性腸徵候簇（IBS)，譬如主要為便秘之IBS、主要為腹瀉 之IBS或主要為交替排便之IBS。舉例之刺激性腸徵候簇 (IBS)與功能性胃腸病症，譬如功能性消化不良，係說明於 Thompson WG3 Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muelle r-Lissner SA. C.功能性腸病症與功能性腹痛，在：Drossman DA， Talley NJ，Thompson WG，Whitehead WE，Coraziarri E 編著，Rome II : 功能性胃腸病症：診斷，病理生理學及治療，第2版，McLean， VA : Degnon 聯合公司；2000 : 351-432 及 Drossman DA，Corazziari E， Talley NJ，Thompson WG 及 Whitehead WE，Rome II:關於功能性胃腸 病症之多國同感文件，Gut45 (補充2)，II1-II81.9-1-1999中。 亦在本發明之範圍内者係為根據上文式I之任何化合物 於藥劑製造上之用途，該藥劑係用於治療任何上文所討論 之症狀。 本發明之進一步方面係為一種治療患有任何上文所討論 症狀之病患之方法，而其中係將有效量之根據上文式I之化 101539 -27- 200539856 合物投予需要此種治療之病患。 因此’本發明係提供如前文定義之式I化合物或其藥學上 可接受之鹽或溶劑合物，供使用於療法上。 於進一步方面，本發明係提供如前文定義之式I化合物或 其藥學上可接受之鹽或溶劑合物在用於療法之藥劑製造上 之用途。 就本專利說明書而論，"療法，，一詞亦包括"預防，，，除非 有相反之特定指示。”治療”與"治療上"術語應據此解釋。 於本發明之内文中，”療法”一詞係進一步涵蓋投予有效量 之本發明化合物，以緩和無論是先前存在之急性或慢性疾 病狀態，或複發症狀。此定義亦涵蓋預防療法，以預防複 發症狀，及對慢性病症之持續治療。 本發明化合物可用於療法，尤其是各種疼痛症狀之療 法，包括但不限於.急性疼痛、慢性疼痛、神經病原性疼 痛、背痛、癌症疼痛及内臟疼痛。 在用於溫血動物譬如人類中之療法時，本發明之化合物 可以習用醫藥組合物形式，藉由任何途徑，包括經口方式、 肌内方式、皮下方式、局部方式、鼻内方式、腹膜腔内方 式、胸内方式、靜脈内方式、硬膜外方式、鞘内方式、腦 室内方式’及藉由注射至關節中投藥。 於本U之-項具體實施例巾，投藥途徑可為口服、靜 脈内或肌内。 當決定在對於最適合特定病患下之個別服用法與劑量程 度時’劑量係依投藥途徑、疾病之嚴重性、病患之年齡與 101539 -28- 200539856 體重’及-般由負責醫師所考慮之其他因素而定。 對於自本發明化合物製備醫藥組合物，惰性藥學上可接 ^載劑可為固體與液體之任u體形式製劑包括粉 末、片劑、可分散顆粒、膠囊、扁囊劑及栓劑。 固體載劑可為一或多種物質，其亦可充作稀釋劑、矯味 劑、增溶劑、潤滑劑、懸浮劑、黏合劑或片劑崩解劑；其 亦可為包膠物質。The compounds of the invention are useful as analgesics for use during general anesthesia and monitoring anesthesia care. Combinations of agents with different properties are often used to achieve the balance of effects needed to maintain anesthesia (such as memory loss, analgesia, muscle relaxation, and sedation). Included in this combination are narcotics® r agents, sleeping pills, anxiolytics, neuromuscular blockers, and opioids. Another aspect of the invention is the use of a compound according to formula for inhibiting transient muscle relaxation (TLESR), and thus for the treatment or prevention of gastric and esophageal reflux disease (GERD). The main mechanism behind reflux has been considered to depend on the birth of the esophageal sphincter by hypotension. However, for example, Hollow # & D⑼t (1990) Gastr0enter〇i_ ain N Amer 19, p. 517 · 535, it has been confirmed that most of the responses " L occur incidentally during the transient lower esophageal sphincter relaxation (TLESR). Qi and relaxation are not triggered by swallowing. In further specific embodiments, the compounds according to the present invention can be used to prevent reflux, treat or prevent nausea, treat or prevent asthma, treat or prevent laryngitis, treat or prevent lung disease, and treat undeveloped health. 101539 • 26-200539856 A further aspect of the present invention is the use of a compound of formula i for the manufacture of a medicament for inhibiting transient lower esophageal sphincter relaxation for the treatment or prevention of GERD, prevention of reflux, treatment or prevention of nausea, treatment Or prevent asthma, treat or prevent laryngitis, treat or prevent lung disease, and manage failure to thrive. A further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of a functional gastrointestinal disorder, such as functional dyspepsia (FD). Yet another aspect of the present invention is the use of a compound of formula I in the manufacture of a medicament for treating or preventing irritating bowel syndrome (IBS), such as IBS mainly constipation, IBS mainly diarrhea Or mainly IBS with alternating defecation. Examples of irritable bowel syndrome (IBS) and functional gastrointestinal disorders, such as functional dyspepsia, are described in Thompson WG3 Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muelle r-Lissner SA. C. Functional bowel Illnesses and Functional Abdominal Pain in: Drossman DA, Talley NJ, Thompson WG, Whitehead WE, Coraziarri E, Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment, 2nd Edition, McLean, VA: Degnon Combination Company; 2000: 351-432 and Drossman DA, Corazziari E, Talley NJ, Thompson WG and Whitehead WE, Rome II: Multinational Sympathy Document on Functional Gastrointestinal Disorders, Gut45 (Suppl. 2), II1-II81.9-1 -1999. Also within the scope of the present invention is the use of any compound according to formula I above in the manufacture of a medicament for the treatment of any of the symptoms discussed above. A further aspect of the invention is a method of treating a patient suffering from any of the symptoms discussed above, wherein an effective amount of a compound according to Formula I 101539 -27- 200539856 above is administered in need of such treatment Patient. Thus, the present invention provides a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy. In a further aspect, the invention provides the use of a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for use in therapy. For the purposes of this patent specification, the term " therapy, " also includes " prevention, " unless specifically instructed to the contrary. The terms "treatment" and "therapeutic" should be interpreted accordingly. In the context of the present invention, the term "therapy" further encompasses the administration of an effective amount of a compound of the present invention to alleviate either a pre-existing state of an acute or chronic disease, or relapse symptoms. This definition also covers preventive therapies to prevent recurrent symptoms and continuous treatment of chronic conditions. The compounds of the present invention are useful in therapies, especially in the treatment of various pain symptoms, including, but not limited to, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain. When used in warm-blooded animals such as humans, the compounds of the present invention can be used in the form of conventional pharmaceutical compositions by any route, including oral, intramuscular, subcutaneous, topical, intranasal, and peritoneal cavity. Intravenous, intrathoracic, intravenous, epidural, intrathecal, intraventricular, and by injection into the joint. In the embodiment of this U-item, the administration route can be oral, intravenous or intramuscular. When deciding on the individual dosage and dosage level that is most suitable for a particular patient, the 'dose depends on the route of administration, the severity of the disease, the age of the patient and 101539 -28- 200539856 weight' and-generally considered by the responsible physician Depending on other factors. For the preparation of pharmaceutical compositions from the compounds of the present invention, inert pharmaceutically acceptable carriers can be in solid or liquid form, including powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier may be one or more substances, and it may also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrating agent; it may also be an encapsulating substance.

在粉末中’ _為細分固體，其係在於與本發明之細分 化合物或活性成份之混合物中。在片劑中，係將活性成: 與具有必要點結性質之載劑，以適當比例混合， 所要之形狀與大小。 成 關於製備栓劑組合物’係首先熔解低熔點蠟，譬如脂肪 酸甘油醋與可可豆脂之混合物’並藉由例如攪拌：使活性 成份t散於其中。然後，將炼融態均勻混合物倒人合宜大 小之模具中，並使其冷卻與固化。 適當載劑為碳酸鎂、硬脂酸鎂、滑石、乳糖、糖、果膠、 糊精n西頁蓍樹膠、甲基纖維素、叛甲基纖維素納、 低炼點壤、可可豆脂等。 組合物-詞亦意欲包括活性成份與作為載體之包膠物質 之配方’該包膠物質係提供膠囊，其中活性成份（使用或未 /、他載μ )係被載體圍繞’此載體因此係與其締合。同 樣地’扁囊劑係被包含在内。 片劑、粉末、扁囊劑及膠囊可作為適於口服投藥之固體 劑型使用。 101539 -29- 200539856 液體形式組合物包括溶液、懸浮液及乳化液。例如，活 性化合物之無菌水或水/丙二醇溶液可為適用於非經腸投 藥之液體製劑。液體組合物亦可經調配而溶解在聚乙二醇 水溶液中。 供口服投藥之水溶液可經由使活性成份溶解於水中，並 按需要添加適當著色劑、矯味劑、安定劑及增稠劑而製成。 供口服使用之含水懸浮液’可經由使細分活性成份與黏稍 物質一起分散於水中而製成，該物質譬如天然合成膠質、 樹脂、甲基纖維素、羧甲基纖維素鈉及醫藥配方技藝2知 之其他懸浮劑。 依投藥模式而定，醫藥組合物較佳係包含005%至99〇加 (重量百分比）’更佳為0.10至50%w之本發明化合物所有 重量百分比均以全部組合物為基準。'_ In the powder is a finely divided solid, which is in a mixture with the finely divided compound or active ingredient of the present invention. In tablets, the activity is: mixed with a carrier with the necessary knotting properties in the appropriate proportions, the desired shape and size. With regard to the preparation of suppository composition ', a low-melting wax such as a mixture of fatty acid glycerol vinegar and cocoa butter is first melted and the active ingredient t is dispersed therein by, for example, stirring. Then, pour the homogeneous mixture in the molten state into a mold of appropriate size, and allow it to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin n-page gum, methylcellulose, methylcellulose sodium, low-refined soil, cocoa butter, etc. . Composition-The word is also intended to include a formulation of the active ingredient and an encapsulating substance as a carrier 'the encapsulating substance is provided in a capsule in which the active ingredient (used or not /, other contained μ) is surrounded by the carrier' This carrier is therefore related to Associate. Similarly, a cachet is included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. 101539 -29- 200539856 Liquid form compositions include solutions, suspensions and emulsions. For example, a sterile water or water / propylene glycol solution of the active compound may be a liquid preparation suitable for parenteral administration. The liquid composition can also be formulated to be dissolved in an aqueous polyethylene glycol solution. The aqueous solution for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavoring agents, stabilizers and thickeners as needed. Aqueous suspensions for oral use can be prepared by dispersing finely divided active ingredients in water together with viscous substances such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and pharmaceutical formulating techniques 2 Known other suspending agents. Depending on the mode of administration, the pharmaceutical composition preferably comprises from 005% to 990 plus (weight percent) ', more preferably from 0.10 to 50% w. All weight percentages are based on the entire composition.

用於實施本發明之治療上有效量，可利用已知標準測定， 包括個別病患之年齡、體重及回應’並藉由此藝一般技術 之-，在關於正被治療或預防之疾病論點内解釋。 之範圍内者，係為任何如上文定義之式1化合物 於樂劑製造上之用途。 藥劑製造 亦在本發明之範圍内者，係為任何式！化合物於 上之用途，該藥劑係用於治療疼痛。 於藥劑製造上之用 包括但不限於··急 背痛、癌症疼痛及 另外提供者為根據式〗之任何化合物 途LMm療各種疼痛症狀， 性疼痛、慢性疼痛、神經病原性疼痛、 内臟疼痛。 101539 -30- 200539856 本發明之進_步—方面’係為—種治療患有任何上文所 u狀之病患之方法，其中係將有效量之根據上文式工 之化合物投予需要此種治療之病患。 —此外，其係提供一種醫藥組合物，其包含式I化合物或其 藥子上可接欠之鹽，伴隨著藥學上可接受之載劑。A therapeutically effective amount for implementing the present invention can be determined using known standards, including the age, weight, and response of individual patients, and by the general techniques of this art, within the argument about the disease being treated or prevented Explanation. Within this range is any use of a compound of formula 1 as defined above for the manufacture of tinctures. Pharmaceutical manufacturing is also within the scope of the present invention, any formula! The compound is used for the treatment of pain. The use in the manufacture of pharmaceuticals includes but is not limited to ... acute back pain, cancer pain and other providers who use any compound according to formula LMm to treat various pain symptoms, sexual pain, chronic pain, neuropathic pain, visceral pain . 101539 -30- 200539856 A further aspect of the present invention is a method for treating a patient suffering from any of the conditions described above, wherein an effective amount of a compound according to the above formula is needed to administer this This kind of treatment for patients. -Furthermore, it provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, accompanied by a pharmaceutically acceptable carrier.

特定口之其係提供_種醫藥組合物，其包含式I化合物 或其藥學上可接受之鹽’伴隨著藥學上可接受之載劑，以 用於治療，更特別是疼痛之治療。The specific mouthpiece provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof 'together with a pharmaceutically acceptable carrier for the treatment, more particularly the treatment of pain.

再者/、係提i、 _醫藥組合物，其包jg J 藥學t:接受之鹽，伴隨著藥學上可接受之載劑，用於： 文所討論之任何症狀。 本發明之另一方面，作兔 ^ 係為一種製備本發明化合物之方 本發明之方法係為製備式I化合物Furthermore, /, is a pharmaceutical composition, including jg J, pharmaceutical t: accepted salt, accompanied by a pharmaceutically acceptable carrier, for: any of the symptoms discussed herein. In another aspect of the present invention, the rabbit is a method for preparing the compound of the present invention. The method of the present invention is to prepare a compound of the formula I

於一項具體實施例中，太麻 之方法In a specific embodiment, the method is too numb

其包括使式π化合物 〇It involves making a compound of formula π.

101539 -31 - 200539856 與R3(CH2)nR4NH化合物，於鹼譬如DIPEA，溶劑譬如DMF， 及視情況選用之偶合試劑譬如H ATU存在下反應之步驟， 其中： m係選自0, 1及2 ; η係選自0，1，2,3,4及5 ; R1係獨立選自鹵素、氰基、胺基、硝基、Ci-6烷胺基、 二Ci_6烷胺基、乙醯胺基、羥基、Ci_6烷氧基、（：卜6烷基、 鹵化烷氧基、（V6烯基及函化烷基； R2係選自C6-10芳基與C2-10雜環基；其中該用於定義R2之 C6-10芳基與C2_10雜環基，係視情況被一或多個基團取代， 該基團係選自鹵素、鹵化q-6烷基、（^_6烷基、氰基、硝基、 q-6烷氧基、鹵化（^_6烷氧基、羥基、羥基烷基、胺基、 烷氧基-Ci-6烷基、Cy烷羰基、烷氧羰基、（V6烷 胺基、二Cu烷基-胺基、胺基-Ci-6烷基、C2-5雜環基-Ch 烷基、0：3-6環烷基、C2-6雜芳基、雜芳基-Cm烷基、C6_1() 芳基及C6_10芳基烷基；且 R3係選自氫與Ci-6烷基；R4係選自CV6烷基、C3-7環烷 基' C4-7環烯基、C6-10芳基、C2_6雜環基-胺基、C2_6雜環基 氧基-胺基及C2_6雜環基；其中該用於定義R4之烷基、 C3 - 7 $衣院基、C4 - 7壞稀基、Cg -1 〇芳基、C2 · 6雜環基-胺基、 C2-6雜環基氧基-胺基及c2-6雜環基，係視情況被一或多個 基團取代，該基團係選自鹵素、鹵化Ci-6烷基、<^-6烷基、 氰基、硝基、Ci-6烷氧基、鹵化Ci-6烷氧基、羥基、羥基-Ci_6 烷基、胺基、Ch烷氧基烷基、Ci-6烷羰基、Cw烷氧 101539 -32- 200539856 羰基、Ch6烷胺基、二Ch烷基-胺基、胺基_Ch烷基、c3_6 環烷基、c2_6雜芳基、雜芳基-Cu烷基、C6-10芳基及c6.1() 芳基-C!-6烧基；或 知 、R3 係選自C2 - 1 Q雜ί哀基’其係 視情況被一或多個基團取代，該團基係選自鹵素、_素取 代之q-6烷基、Q — 6烷基、氰基、硝基、Ci-6烷氧基、鹵化 Ci-6烷氧基、羥基、羥基烷基、胺基、c1-6烷氧基七Η 烷基、Cle6烷羰基、Ci-6烷氧羰基、cle6烷胺基、二C16烷 基·胺基、胺基-Ch烧基、（：3·6環烷基、c26雜芳基、雜芳 基（1-6烧基、C6-10芳基及Cg-io芳基_C1-6燒基。101539 -31-200539856 and R3 (CH2) nR4NH compounds in the presence of a base such as DIPEA, a solvent such as DMF, and optionally a coupling reagent such as H ATU, wherein: m is selected from 0, 1 and 2; η is selected from 0,1,2,3,4 and 5; R1 is independently selected from halogen, cyano, amine, nitro, Ci-6 alkylamino, di Ci-6 alkylamino, acetamido, Hydroxyl, Ci_6 alkoxy, (: P6 alkyl, halogenated alkoxy, (V6 alkenyl and functional alkyl); R2 is selected from C6-10 aryl and C2-10 heterocyclyl; where this is used for The C6-10 aryl group and C2_10 heterocyclic group of R2 are optionally substituted by one or more groups selected from the group consisting of halogen, halogenated q-6 alkyl, (^ _6 alkyl, cyano, Nitro, q-6 alkoxy, halogenated (^ -6 alkoxy, hydroxy, hydroxyalkyl, amine, alkoxy-Ci-6 alkyl, Cy alkylcarbonyl, alkoxycarbonyl, (V6 alkylamino) , DiCu alkyl-amino, amino-Ci-6 alkyl, C2-5 heterocyclyl-Ch alkyl, 0: 3-6 cycloalkyl, C2-6 heteroaryl, heteroaryl-Cm Alkyl, C6_1 () aryl and C6_10 arylalkyl; and R3 is selected from hydrogen and Ci-6 alkyl; R4 is selected from CV6 alkyl C3-7 cycloalkyl 'C4-7 cycloalkenyl, C6-10 aryl, C2-6 heterocyclyl-amino, C2-6 heterocyclyloxy-amino and C2-6 heterocyclyl; where this is used to define R4 Alkyl, C3-7 $ Yuanji, C4-7Bao diyl, Cg-1oaryl, C2-6 heterocyclyl-amine, C2-6heterocyclyloxy-amine and c2-6 Heterocyclic group, optionally substituted by one or more groups, the group is selected from halogen, halogenated Ci-6 alkyl, < -6 alkyl, cyano, nitro, Ci-6 alkoxy Group, halogenated Ci-6 alkoxy group, hydroxyl group, hydroxy-Ci_6 alkyl group, amine group, Ch alkoxyalkyl group, Ci-6 alkylcarbonyl group, Cw alkoxy group 101539 -32- 200539856 carbonyl group, Ch6 alkylamino group, two Ch alkyl-amino, amine-Ch alkyl, c3-6 cycloalkyl, c2-6 heteroaryl, heteroaryl-Cu alkyl, C6-10 aryl, and c6.1 () aryl-C! -6 Alkyl; or R3 is selected from the group consisting of C2-1 Q hetero, and it is optionally substituted by one or more groups, the group is selected from the group consisting of halogen, q-6 alkyl, Q — 6 alkyl, cyano, nitro, Ci-6 alkoxy, halogenated Ci-6 alkoxy, hydroxyl, hydroxyalkyl, amine, c1-6 alkoxy heptamyl, Cle6 alkylcarbonyl , Ci-6 alkoxycarbonyl, cle6 alkylamino, diC16 alkyl · amino, amine-Ch alkyl, (3.6 cycloalkyl, c26 heteroaryl, heteroaryl (1-6 alkyl) C6-10 aryl and Cg-io aryl_C1-6 alkyl.

製備。 囷式1·用於合成化合物之合成途徑preparation.囷 Formula 1 · Synthetic pathway for synthesizing compounds

〇八R2〇Eight R2

鹼，例如DIPEA 溶劑，例如ch2ci2 當Υ=0Η時 鹼，例如DIPEA 溶劑，例如DMF 偶合試劑，例如HATUBase, such as DIPEA solvent, such as ch2ci2 when Υ = 0Η base, such as DIPEA solvent, such as DMF coupling reagent, such as HATU

_，例如 DIPEA 溶劑，例如DMF 偶合試劑，例如HATU 101539 R3、N,(CH2)nR4_, Such as DIPEA solvents, such as DMF coupling reagents, such as HATU 101539 R3, N, (CH2) nR4

•33- 200539856 圖式2·用於合成化合物之合成途徑 R1• 33- 200539856 Scheme 2 · Synthetic pathway R1 for compound synthesis

C02H nh2C02H nh2

R2COY 當Y=C1時 鹼，例如DIPEA 溶劑，例如ch2ci2R2COY when Y = C1 base, such as DIPEA solvent, such as ch2ci2

當Υ=0Η時 鹼，例如DIPEA 溶劑，例如DMF 偶合試劑，例如HATUWhen Υ = 0Η Alkali, such as DIPEA solvent, such as DMF coupling reagent, such as HATU

鹼，例如DIPEA 溶劑，例如DMF 偶合試劑，例如HATU ΟBases, such as DIPEA solvents, such as DMF coupling reagents, such as HATU Ο

R3R4(CH2)nNHR3R4 (CH2) nNH

鹼，例如DIPEA 溶劑，例如DMF R3、NXCH2)nR4Base, such as DIPEA solvents, such as DMF R3, NXCH2) nR4

圖式3.用於合成化合物之合成途徑 〇Scheme 3. Synthetic pathways used to synthesize compounds

R3R4(CH2)nNH R3、N,(CH2)nR4 ΗR3R4 (CH2) nNH R3, N, (CH2) nR4 Η

鹼，例如DIPEA 溶劑，例如DMF R3、N,(CH2)nR4Bases, such as DIPEA solvents, such as DMF R3, N, (CH2) nR4

R2COYR2COY

當Y=C1時 鹼，例如DIPEA 溶劑，例如CH2CI2 當Υ=0Η時 鹼，例如DIPEA 溶劑，例如DMF 偶合試劑，例如HATU 生物學評估 ^丑^與hCB2^體結合 使得自Receptor Biology之人類CBi受體（hCB!)，或得自 BioSignal之人類CB2受體（hCB2)細胞膜於37°C下融解，通過25 號純端針頭3次，於類大蔴苷結合緩衝劑（50 mM Tris，2.5 mM £〇丁八，5111]\41^(：12及0.5毫克/毫升不含脂肪酸之83入$117.4) 101539 -34- 200539856 中稀釋，並將含有適當蛋白質量之液份分配在96-井板中。 本發明化合物在冗81與1^62上之IC5〇，係由10-點劑量-回應 曲線評估，以 3 H-CP55,940，於每井 20000 至 25000 dpm (0.17-0.21 nM)下，在最後體積300微升中進行。總結合與非專一性結 合係個別於0.2 //MHU210不存在與存在下測定。使此等板形 成渦動，並在室溫下培養60分鐘，使用3毫升洗蘇緩衝劑 (50mMTris，5mMMgCl2,0.5 毫克 BSApH7.0)，過濾經過具有 Tomtec或Packard採集器之Unifilters GF/B (經預浸泡在0.1%聚乙 烯亞胺中）。使濾器於55°C下乾燥1小時。於添加65微升/井 MS-20閃爍液體後，在TopCount(Packard)中計數放射活性 (cpm) ° hCBLj^ hCBfTP yS 結合 使得自Receptor Biology之人類CBi受體（hCBi)，或人類CB2 受體細胞膜（BioSignal)於37°C下融解，通過25號鈍端針頭3 次，並在 GTP yS 結合緩衝劑（50 mM Hepes，20 mM NaOH，100 mM NaCl，1 mM EDTA，5 mM MgCl2，pH 7.4, 0.1% BSA)中稀釋。本發明 化合物之EC50與Emax係由10-點劑量回應曲線評估，在300 微升中，以適當量膜蛋白質與每井100000-130000dpmGTPg35S (0.11-0.14 nM)進行。基底與最高刺激之結合，係個別於1 /z M (hCB2)或10 /zM (hCB!) Win 55,212-2不存在與存在下測定。於 分佈在板（最後15 //M(hCB2)或30 aMOiCBDGDP)中之前，使 細胞膜與 56.25 #M(hCB2)或 112_5 //MChCBOGDP 預培養 5 分 鐘。使此等板形成渦動，並於室溫下培養60分鐘，使用3 毫升洗滌缓衝劑（50 mM Tris，5 mM MgCl2，50 mM NaCl，pH 7.0)，在 101539 -35- 200539856 具有Tomtec或Packard採集器之Unifilters GF/B (經預浸泡在水 中）上過濾。使濾器於55°C下乾燥1小時。於添加65微升/井 MS-20閃燦液體後，在TopCount (Packard)中計數放射活性 (cpm)。拮抗劑逆轉研究係以相同方式完成，惟⑻催動劑劑 量-回應曲線係於固定濃度之拮抗劑存在下完成，或（b)拮抗 劑劑量-回應曲線係於固定濃度之催動劑存在下完成。 以上述檢測為基礎，本發明特定化合物針對特定受體之 解離常數（Ki)係使用下列方程式測定：When Y = C1, a base such as DIPEA solvent, such as CH2CI2 When Υ = 0, a base, such as DIPEA solvent, such as DMF coupling reagent, such as HATU Biological evaluation ^ Ugly ^ combined with hCB2 ^ body makes human CBi from Receptor Biology affected (HCB!), Or the human CB2 receptor (hCB2) cell membrane obtained from BioSignal, was thawed at 37 ° C, passed through a 25-gauge needle 3 times, and in a cannabinoid-like buffer (50 mM Tris, 2.5 mM £ 〇 Dingba, 5111] \ 41 ^ (: 12 and 0.5 mg / ml of fatty acid-free 83 into $ 117.4) 101539 -34- 200539856, and the liquid containing the appropriate protein quality was distributed in 96-well plates. The IC50 of the compound of the present invention on Redundant 81 and 1 ^ 62 was evaluated from a 10-point dose-response curve with 3 H-CP55,940 at 20,000 to 25,000 dpm (0.17-0.21 nM) per well at The final volume was carried out in 300 microliters. The total binding and non-specific binding were measured separately in the absence and presence of 0.2 // MHU210. The plates were vortexed and incubated for 60 minutes at room temperature. Wash with 3 ml Buffer (50mM Tris, 5mMMgCl2, 0.5 mg BSA pH7.0), filtered through with Tomtec or Packa Unifilters GF / B of the rd collector (pre-soaked in 0.1% polyethyleneimine). Allow the filter to dry at 55 ° C for 1 hour. After adding 65 μl / well MS-20 scintillation liquid, topCount ( Packard) counts the radioactivity (cpm) ° hCBLj ^ hCBfTP yS binding allows the human CBi receptor (hCBi) or human CB2 receptor cell membrane (BioSignal) from Receptor Biology to melt at 37 ° C and pass through a 25-gauge blunt-ended needle 3 times and diluted in GTP yS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, 0.1% BSA). The EC50 and Emax of the compounds of the present invention are 10-point dose-response curve evaluation was performed in 300 microliters with an appropriate amount of membrane protein and 100,000-130000 dpm GTPg35S (0.11-0.14 nM) per well. The combination of basal and highest stimuli was individually 1 / z M (hCB2) Or 10 / zM (hCB!) Win 55,212-2 is determined in the absence and presence. Before distributing in the plate (last 15 // M (hCB2) or 30 aMOiCBDGDP), the cell membrane is contacted with 56.25 #M (hCB2) or 112_5 // MChCBOGDP pre-culture for 5 minutes. These plates were vortexed and incubated at room temperature for 60 minutes using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0), with Tomtec or Packard at 101539 -35- 200539856 Collectors are filtered on Unifilters GF / B (pre-soaked in water). The filter was allowed to dry for 1 hour at 55 ° C. After adding 65 μl / well of MS-20 Brilliant Liquid, radioactivity (cpm) was counted in TopCount (Packard). Antagonist reversal studies were done in the same way, except that the stimulant dose-response curve was completed in the presence of a fixed concentration of antagonist, or (b) the antagonist dose-response curve was in the presence of a fixed concentration of activator carry out. Based on the above detection, the dissociation constant (Ki) of a specific compound of the present invention for a specific receptor is determined using the following equation:

Ki = IC5〇/(l+[rad]/Kd)， 其中IC5〇為本發明化合物在已發現50%置換下之濃度； [rad]為該時刻之標準或參考放射性配位體濃度；且 Kd為放射性配位體針對特定受體之解離常數。 使用上文所提及之檢測，度量出大部份本發明化合物針 對人類CBi受體之Ki，係在7.3-5900 nM之範圍内。度量出大 部份本發明化合物針對人類CB2受體之Ki，係在約 4.7-5300 nM之範圍内。度量出大部份本發明化合物針對人類 CBi受體之EC5〇，係在約40-6500 ηΜ之範圍内。度量出大部份 本發明化合物針對人類CBi受體之Emax，係在約17.7-110%之 範圍内。 下表係說明關於一些舉例化合物之某些生物學活性。 化合物 結構 Ki (hCBl) (nM) EC50 (hCBl) (nM) Emax (hCBl) (%) 實例49 。为 179 968 109 101539 -36- 200539856 實例30 切0 71 304 109 實例17 7.3 41 95 」 【實施方式】 實例 本發明將藉下述實例進一步更詳細地描述，其係描述本 • 發明化合物可藉以製備、純化、分析及生物學上測試之方 法，且其並非欲被解釋為限制本發明。 實例1 N-[4-氣基-2-[[[(l-乙基-2-四氫吡咯基）甲基;|胺基]羰基]苯基]+ 莕羧醯胺Ki = IC50 / (l + [rad] / Kd), where IC50 is the concentration of the compound of the present invention at which 50% substitution has been found; [rad] is the standard or reference radioligand concentration at that time; and Kd is Dissociation constant of a radioligand against a specific receptor. Using the tests mentioned above, the Ki of most compounds of the invention for human CBi receptors was measured in the range of 7.3-5900 nM. The Ki of most of the compounds of the present invention against the human CB2 receptor was measured in the range of about 4.7-5300 nM. The EC50 of most compounds of the invention against human CBi receptors was measured in the range of about 40-6500 nM. The Emax of most compounds of the present invention against human CBi receptors was measured in the range of about 17.7-110%. The following table illustrates certain biological activities with respect to some exemplary compounds. Compound Structure Ki (hCBl) (nM) EC50 (hCBl) (nM) Emax (hCBl) (%) Example 49. For 179 968 109 101539 -36- 200539856 Example 30 Cut 0 71 304 109 Example 17 7.3 41 95 "[Embodiments] Examples The present invention will be described in more detail by the following examples, which describe the present invention compounds can be prepared by , Purification, analysis, and biological testing methods, and are not intended to be construed as limiting the invention. Example 1 N- [4-Amino-2-[[[(l-ethyl-2-tetrahydropyrrolyl) methyl; | amino] carbonyl] phenyl] + carbamidine

步驟Α· N-[4-氣基-2_[[[(1-乙基-2-四氫吡咯基）甲基]胺基]Μ基] 苯基]-1-茶羧醯胺Step A · N- [4-Gasyl-2 _ [[[(1-ethyl-2-tetrahydropyrrolyl) methyl] amino] M group] phenyl] -1-teacarboxamide

於室溫下，將1-乙基-2-四氫吡咯曱胺（156·0毫克’ 1.22毫莫 101539 -37- 200539856 耳）添加至5-氣基-2-[(l-莕基羰基）胺基]_苯甲酸（200.0毫克， 〇·61毫莫耳，關於其製備可參閱步驟6)與HATU (257.0毫克， 〇·68毫莫耳）之DMF (5毫升）溶液内。將反應混合物攪拌過 夜，然後在真空中濃縮。使殘留物藉由逆相HPLC，使用 20-80%CH3CN/H20純化，接著凍乾，以提供標題化合物，為 其相應之 TFA 鹽（76 毫克，23%)。iHNMRGOOMHz’CDC^) 5 1.31 (t，J=7.23 Hz，3H)，1·86 (m，1H)，2.07 (m，2H)，2.19 (m，1H)，2·95 (m， 4H)，3.20 (s，1H)，3·57 (m，1H)，3.81 (m，1H)，7·55 (m，4H)，7·83 (d，J=6.25 Hz，1H)，7·87 (m，2H)，7.97 (d，J=8.20 Hz，1H)，8·49 (s，1H)，8.92 (d，J=8.98 Hz，1H)，9.54 (s，1H)，12.04 (s，1H)· MS (ESI) (M+H)+436.1. 步驟B· 5-氣基-2_[(1-莕基羰基）胺基]-苯甲酸At room temperature, add 1-ethyl-2-tetrahydropyrrolidine (156.0 mg '1.22 mmol 101539 -37- 200539856 ear) to 5-amino-2-[(l-fluorenylcarbonyl) ) Amino] -benzoic acid (200.0 mg, 0.61 mmol, see step 6) for its preparation in a solution of HAMF (257.0 mg, 0.68 mmol) in DMF (5 ml). The reaction mixture was stirred overnight and then concentrated in vacuo. The residue was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (76 mg, 23%). iHNMRGOOMHz'CDC ^) 5 1.31 (t, J = 7.23 Hz, 3H), 1.86 (m, 1H), 2.07 (m, 2H), 2.19 (m, 1H), 2.95 (m, 4H), 3.20 (s, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 7.55 (m, 4H), 7.83 (d, J = 6.25 Hz, 1H), 7.87 ( m, 2H), 7.97 (d, J = 8.20 Hz, 1H), 8.49 (s, 1H), 8.92 (d, J = 8.98 Hz, 1H), 9.54 (s, 1H), 12.04 (s, 1H ) · MS (ESI) (M + H) + 436.1. Step B · 5-Amino-2 _ [(1-fluorenylcarbonyl) amino] -benzoic acid

在〇°C下，將1-莕羰基氣（97微升，0.64毫莫耳）在CH2C12(毫 升）中之溶液，添加至2-胺基5-氣苯曱酸（110毫克，〇·64毫莫 耳）與三乙胺（90微升，0.64毫莫耳）在CH2C12 (3.5毫升）中之混 合物内。然後，將反應混合物於室溫下攪拌過夜。於移除 溶劑後，將固體以H20洗滌，收集，並在真空中乾燥，以 提供標題化合物（200毫克，95%)。iHNMRGOOMHz'DClJ 5 7.59 (m，2H)，7.67 (m，1H)，7·75 (d，J=8.59 Hz，1H)，7.81 (m，1H)，7.94 (d，J= 8.20 Hz, 1H), 8.07 (d, J=8.20 Hz, 1H), 8.26 (d5 J=2.15 Hz, 1H)3 8.33 (d5 J= 7·23 Hz，1H)，9.13 (d，J=8.79 Hz，1H). MS (ESI) (M+H)+ 326. 101539 -38- 200539856 實例2 N-[4-氯基-2-[[[2-(4-嗎福啉基）乙基]胺基]羰基]苯基]-1-莕羧醯胺At 0 ° C, a solution of 1-fluorene carbonyl gas (97 µl, 0.64 mmol) in CH 2 C 12 (ml) was added to 2-amino 5-gas benzoic acid (110 mg, 0.64 Mmol) and triethylamine (90 μl, 0.64 mmol) in CH2C12 (3.5 ml). The reaction mixture was then stirred at room temperature overnight. After removing the solvent, the solid was washed with H20, collected, and dried in vacuo to provide the title compound (200 mg, 95%). iHNMRGOOMHz'DClJ 5 7.59 (m, 2H), 7.67 (m, 1H), 7.75 (d, J = 8.59 Hz, 1H), 7.81 (m, 1H), 7.94 (d, J = 8.20 Hz, 1H) , 8.07 (d, J = 8.20 Hz, 1H), 8.26 (d5 J = 2.15 Hz, 1H) 3 8.33 (d5 J = 7.23 Hz, 1H), 9.13 (d, J = 8.79 Hz, 1H). MS (ESI) (M + H) + 326. 101539 -38- 200539856 Example 2 N- [4-Chloro-2-[[[[2- (4-morpholinyl) ethyl] amino] carbonyl] benzene Yl] -1-carbamidine

按照實例1中步驟Α之程序，使用DMF (5毫升）中之5-氣基 -2-[(l-莕基羰基）胺基]-苯甲酸(200.0毫克，0·61毫莫耳）、HATU (257.0毫克，0·68毫莫耳）及4-嗎福啉乙胺（160微升，1.22毫莫 耳）。使產物藉由逆相HPLC，使用20-80%CH3CN/H20純化， 然後凍乾，以提供標題化合物，為相應之TFA鹽（58毫克， 17%) 〇 1H NMR (400 MHz, CDC13 ) δ 3.24 (m, 2Η), 3.81 (m, 2H), 3.93 (m, 8H)，7.56 (m，3H)，7·68 (d，J=2.34 Hz，2H)，7·85 (dd，J=7.13, 1.07 Hz，1H)， 7.89 (d，J=1.76 Hz，2H)，7.98 (d，J=8.20 Hz，1H)，8.50 (s，1H)，8.87 (d，J= 8·59 Hz，1H)，11.68 (s，1H). MS (ESI) (M+H)+438.1. 實例3 Ν·[4-氯基-2-[[4-[2-(4-嗎福啉基）乙基]小六氫吡畊基]羰基]苯 基莕羧醯胺Following the procedure of step A in Example 1, using 5-amino-2-[(l-fluorenylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU (257.0 mg, 0.68 mmol) and 4-morpholine ethylamine (160 μl, 1.22 mmol). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as the corresponding TFA salt (58 mg, 17%). OH NMR (400 MHz, CDC13) δ 3.24 (m, 2Η), 3.81 (m, 2H), 3.93 (m, 8H), 7.56 (m, 3H), 7.68 (d, J = 2.34 Hz, 2H), 7.85 (dd, J = 7.13 , 1.07 Hz, 1H), 7.89 (d, J = 1.76 Hz, 2H), 7.98 (d, J = 8.20 Hz, 1H), 8.50 (s, 1H), 8.87 (d, J = 8.59 Hz, 1H ), 11.68 (s, 1H). MS (ESI) (M + H) + 438.1. Example 3 Ν · [4-chloro-2--2-[[4- [2- (4-morpholinyl) ethyl ] Small hexahydropyridyl] carbonyl] phenylphosphonium carboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之5-氣基 101539 -39· 200539856 -2-[(l-莕基羰基）胺基]-苯甲酸(2〇〇·〇毫克，0.61毫莫耳）、HATU (257.0毫克，0·68毫莫耳）及4-[2-(l-六氫吡畊基）乙基]-嗎福啉 (243毫克，1·22毫莫耳）。使產物藉由逆相HPLC，使用20-80% CH3CN/H20純化，然後凍乾，以提供標題化合物，為其相 應之 TFA 鹽（67 毫克，18%)。1H NMR (400 MHz, CDC13) (5 2.32 (m， 8H)，3.14 (m，4H)，3·29 (m，2H)，3·37 (m，2H)，3.89 (m，4H)，7.20 (d，J=2.15 Hz，1H)，7.38 (m，1H)，7.50 (m，1H)，7.56 (m，2H)，7.71 (d，J=7.03 Hz，1H)， 7.79 (m，1H)，7.90 (m，1H)，7.98 (d，J=8.20 Hz，1H)，8.32 (s，1H)，8.88 (s， 1H). MS (ESI) (M+H)+507.1. 實例4 N-[4-氣基-2-[[[2-(二甲胺基）乙基]胺基]羰基]苯基]小莕羧醯胺 r\Follow the procedure of Step A in Example 1 using 5-amino group 101539 -39 · 200539856 -2-[(l-fluorenylcarbonyl) amino] -benzoic acid (20.0 mg in DMF (5 ml)) , 0.61 mmoles), HATU (257.0 mg, 0.68 mmoles) and 4- [2- (l-hexahydropyridyl) ethyl] -morpholine (243 mg, 1.22 mmoles ear). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (67 mg, 18%). 1H NMR (400 MHz, CDC13) (5 2.32 (m, 8H), 3.14 (m, 4H), 3.29 (m, 2H), 3.37 (m, 2H), 3.89 (m, 4H), 7.20 (d, J = 2.15 Hz, 1H), 7.38 (m, 1H), 7.50 (m, 1H), 7.56 (m, 2H), 7.71 (d, J = 7.03 Hz, 1H), 7.79 (m, 1H) , 7.90 (m, 1H), 7.98 (d, J = 8.20 Hz, 1H), 8.32 (s, 1H), 8.88 (s, 1H). MS (ESI) (M + H) +507.1. Example 4 N- [4-Amino-2-[[[2- (dimethylamino) ethyl] amino] carbonyl] phenyl] berberylcarboxamide r \

按照實例1中步驟Α之程序，使用DMF (5毫升）中之5-氣基 -2-[(l-莕基羰基）胺基]-苯甲酸(200.0毫克，〇·61毫莫耳）、HATU (257.0毫克，0.68毫莫耳）及Ν，Ν-二甲基-1,2-乙二胺（136微升， 1.22毫莫耳）。使產物藉由逆相hplc，使用20-80% CH3CN/H20 純化，然後凍乾，以提供標題化合物，為其相應之TFA鹽（48 毫克，15%)。iHNMR(400MHz，DMSO-D6)5 2.75(s，6H)，3.18(m， 2H), 3.51 (q5 J=5.79 Hz, 2H), 7.58 (m, 2H), 7.67 (dd5 J=8.79, 2.54 Hz, 1H)5 7.81 (dd，7.03,1.17 Hz，1H)，7.85 (d，>2·34 Hz，1H)，8.00 (m，1H)，8.09 (d，J=8.20 Hz，1H)，8.31 (m，1H)，8.50 (d，J=8.79 Hz，1H)，9.01 (m，1H)，9.28 101539 -40- 200539856 (s，1H)，11.74 (s，1H)· MS (ESI) (M+H)+396· 1· 實例5 N-[4-氣基-2-[(4-嗎福啉基胺基）羰基]苯基]-1-萘羧醯胺Following the procedure of step A in Example 1, using 5-amino-2-[(l-fluorenylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU (257.0 mg, 0.68 mmol) and N, N-dimethyl-1,2-ethylenediamine (136 μl, 1.22 mmol). The product was purified by reverse phase hplc using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (48 mg, 15%). iHNMR (400MHz, DMSO-D6) 5 2.75 (s, 6H), 3.18 (m, 2H), 3.51 (q5 J = 5.79 Hz, 2H), 7.58 (m, 2H), 7.67 (dd5 J = 8.79, 2.54 Hz , 1H) 5 7.81 (dd, 7.03, 1.17 Hz, 1H), 7.85 (d, > 2.34 Hz, 1H), 8.00 (m, 1H), 8.09 (d, J = 8.20 Hz, 1H), 8.31 (m, 1H), 8.50 (d, J = 8.79 Hz, 1H), 9.01 (m, 1H), 9.28 101539 -40- 200539856 (s, 1H), 11.74 (s, 1H) · MS (ESI) (M + H) + 396 · 1 · Example 5 N- [4-Amino-2-[(4-morpholinylamino) carbonyl] phenyl] -1-naphthylcarboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之5-氣基 -2_[(1-莕基羰基)胺基]-苯甲酸(200.0毫克，0.61毫莫耳）、HATU (257.0毫克，0.68毫莫耳）及4-胺基嗎福啉（118微升，1.22毫莫 耳）。使產物藉由逆相HPLC，使用20-80% CH3CN/H20純化， 然後凍乾，以提供標題化合物，為其相應之TFA鹽（51毫克， 16%)。1H NMR (400 MHz，DMSO-D6) 5 2.78 (m，4H)，3.57 (m，4H)，7.57 (m, 3H), 7.70 (m, 1H), 7.79 (dd, J=7.03,1.17 Hz, 1H), 7.98 (m, 2H), 8.08 (d, J=8.20 Hz，1H)，8.30 (dd，J=6.25, 3.51 Hz，1H)，8.36 (d，J=8.98 Hz，1H)， 9.79 (s，1H)，11.42 (s，1H)· MS (ESI) (M+H)+410.0. 實例6 Ν_[4·氣基-2·[(4-乙基-1-六氫吡啡基）羰基]苯基]-μ莕羧醯胺Follow the procedure of step A in Example 1 using 5-amino-2 _ [(1-fluorenylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU (257.0 Mg, 0.68 mmoles) and 4-aminomorpholine (118 µl, 1.22 mmoles). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (51 mg, 16%). 1H NMR (400 MHz, DMSO-D6) 5 2.78 (m, 4H), 3.57 (m, 4H), 7.57 (m, 3H), 7.70 (m, 1H), 7.79 (dd, J = 7.03, 1.17 Hz, 1H), 7.98 (m, 2H), 8.08 (d, J = 8.20 Hz, 1H), 8.30 (dd, J = 6.25, 3.51 Hz, 1H), 8.36 (d, J = 8.98 Hz, 1H), 9.79 ( s, 1H), 11.42 (s, 1H) · MS (ESI) (M + H) +410.0. Example 6 Ν_ [4 · Gasyl-2 · [(4-ethyl-1-hexahydropyridinyl) Carbonyl] phenyl] -μ 荇 carboxamide

按照實例1中步驟Α之程序，使用DMF (5毫升）中之5-氣基 101539 •41 - 200539856Follow the procedure of step A in Example 1 using 5-gas radical in DMF (5 ml) 101539 • 41-200539856

-2-[(l-莕基羰基）胺基]-苯甲酸(200.0毫克，0·61毫莫耳）、HATU (257.0毫克，0·68毫莫耳）及1-乙基六氫吡畊（192微升，1.22毫 莫耳）。使產物藉由逆相HPLC，使用20-80% CH3CN/H20純化， 然後凍乾，以提供標題化合物，為其相應之TFA鹽（64毫克， 20%)〇 ^NMRi^OMHz^DMSO^) δ 1.16 (m, 3Η)5 3.08 (m? 2Η)5 3.25 (s，2Η)，3·52 (m，2Η)，3·84 (m，2Η)，4.47 (m，2Η)，7·43 (d，J=8.40 Ηζ，1Η)， 7.55 (m，4H)，7.58 (d，J=8_20 Hz，1H)，7·67 (m，1H)，7·97 (m，1H)，8·04 (d， J=8.20 Hz，1H)，8.23 (m，1H)，10.68 (s，1H)· MS (ESI) (M+H)+422.1. 實例7 N-[4-氣基-2-[[[3_(4-嗎福啉基）丙基]胺基]羰基]苯基]小萘羧醯胺-2-[(l-fluorenylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol), HATU (257.0 mg, 0.68 mmol), and 1-ethylhexahydropyridine (192 μl, 1.22 millimoles). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (64 mg, 20%). NMRi ^ OMHz ^ DMSO ^) δ 1.16 (m, 3Η) 5 3.08 (m? 2Η) 5 3.25 (s, 2Η), 3.52 (m, 2Η), 3.84 (m, 2Η), 4.47 (m, 2Η), 7.43 ( d, J = 8.40 Ηζ, 1Η), 7.55 (m, 4H), 7.58 (d, J = 8_20 Hz, 1H), 7.67 (m, 1H), 7.97 (m, 1H), 8.04 (d, J = 8.20 Hz, 1H), 8.23 (m, 1H), 10.68 (s, 1H) · MS (ESI) (M + H) +422.1. Example 7 N- [4- 气 基 -2- [ [[3 -_ (4-morpholinyl) propyl] amino] carbonyl] phenyl] naphthylcarboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之5-氣基 •2-[(1_萘基羰基）胺基]-苯甲酸(200.0毫克，0.61毫莫耳）、HATU (257.0毫克，0.68毫莫耳）及4-嗎福啉丙胺（178微升，1·22毫莫 耳）。使產物藉由逆相HPLC，使用20-80% CH3CN/H20純化， 然後凍乾，以提供標題化合物，為其相應之TFA鹽（45毫克， 13%) 〇 1H NMR (400 MHz, DMSO-D6) 5 1.80 (m, 2H), 2.91 (m, 2H), 3.08 (m，2H)，3·23 (m，4H)，3.51 (m，2H)，3.82 (m，2H)，7.57 (m，2H)，7.64 (m， 1H)，7.81 (dd，J=7.42，1.56 Hz，2H)，8.00 (m，1H)，8.09 (d，J=8_20 Hz，1H)， 8.31 (m，1H)，8.49 (d，J=8.79 Hz，1H)，8.98 (s，1H)，9.68 (s，1H)，11.84 (s， 1H). MS (ESI) (M+H)+452.1. 101539 -42- 200539856 實例8與9 N-[4-氣基-2-[[(4-六氫吡啶基甲基）胺基]羰基]苯基]-1-莕羧醯 胺與N-[2-[[4-(胺基甲基）-1-六氫吡啶基]幾基]-4-氯苯基]小莕 羧醯胺Follow the procedure of Step A in Example 1 using 5-amino • 2-[(1-naphthylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU ( 257.0 mg, 0.68 mmoles) and 4-morpholine propylamine (178 µl, 1.22 mmoles). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the title compound as its corresponding TFA salt (45 mg, 13%). OH NMR (400 MHz, DMSO-D6 ) 5 1.80 (m, 2H), 2.91 (m, 2H), 3.08 (m, 2H), 3.23 (m, 4H), 3.51 (m, 2H), 3.82 (m, 2H), 7.57 (m, 2H), 7.64 (m, 1H), 7.81 (dd, J = 7.42, 1.56 Hz, 2H), 8.00 (m, 1H), 8.09 (d, J = 8_20 Hz, 1H), 8.31 (m, 1H), 8.49 (d, J = 8.79 Hz, 1H), 8.98 (s, 1H), 9.68 (s, 1H), 11.84 (s, 1H). MS (ESI) (M + H) +452.1. 101539 -42- 200539856 Examples 8 and 9 N- [4-Amino-2-[[(4-hexahydropyridylmethyl) amino] carbonyl] phenyl] -1-carbamidine and N- [2-[[4 -(Aminomethyl) -1-hexahydropyridyl] Jinyl] -4-chlorophenyl] carboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之5-氣基 莕基羰基）胺基]-苯甲酸(200.0毫克，0.61毫莫耳）、HATU (257.0毫克，0.68毫莫耳）及4-(胺基甲基）六氫吡啶（139毫克， 1.22毫莫耳）。使產物藉由逆相HPLC，使用20-80% CH3CN/H20 純化，然後凍乾，以提供下列兩種化合物： a) . N-[4-氯基-2-[[(4-六氫吡啶基甲基）胺基]羰基]苯基]-1-莕羧 醯胺，為其相應之TFA鹽（25毫克，8%)。iHNMR^OOMHz， DMSO-D6) 5 1·24 (m，2H)，1.73 (m，2H)，2.74 (d，J=8.40 Hz，3H)，3.18 (m， 2H)，3.30 (m，2H)，3.61 (s，1H)，7.57 (m，2H)，7.65 (dd，J=8.88, 2·44 Hz，1H)， 7.78 (dd, J=7.03,1.17 Hz, 1H), 7.83 (d, J=2.34 Hz, 1H), 8.00 (dd, J=6.05, 3.32 Hz，1H)，8.09 (d，J=8.40 Hz，1H)，8.29 (m，1H) 8.39 (s，1H)，8.56 (m， 1H)，8.96 (s，1H)，11.87 (s，1H). MS (ESI) (M+H)+422.1. b) . N-[2-[[4-(胺基曱基）-l_六氫吡啶基]羰基]-4-氣苯基]-1-莕羧 醯胺，為其相應之TFA鹽（32毫克，10%)。^NMRGOOMHz， DMSO-D6) δ 1.25(m,4H), 1.61 (s,2H), 1.74 (m,3H)? 2.65 (m,2H), 4.39 101539 •43- 200539856 (s，2H), 7·38 (d，J=2.54 Hz，1H)，7.50 (m，1H)，7.54 (m，3H)，7.66 (m，2H)， 7.96 (m，1H)，8.02 (m，1H)，8.23 (s，1H)，10.42 (s，1H)· MS (ESI) (M+H)+ 422.1. 實例10與11 N-[2-[[4-(2-胺基乙基）-1-六氫吡畊基]羰基]-4-氣苯基]-l-莕羧醯 胺與Ν-[4-氯基-2-[[[2-(1-六氫吡畊基）乙基]胺基]幾基]苯基]小 莕羧醯胺Follow the procedure of step A in Example 1 using 5-aminofluorenylcarbonyl) amino] -benzoic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU (257.0 mg, 0.68 mmol) ) And 4- (aminomethyl) hexahydropyridine (139 mg, 1.22 mmol). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and then lyophilized to provide the following two compounds: a). N- [4-chloro-2--2-[[(4-hexahydropyridine Methylmethyl) amino] carbonyl] phenyl] -1-fluorencarboxamidine, its corresponding TFA salt (25 mg, 8%). iHNMR ^ OOMHz, DMSO-D6) 5 1.24 (m, 2H), 1.73 (m, 2H), 2.74 (d, J = 8.40 Hz, 3H), 3.18 (m, 2H), 3.30 (m, 2H) , 3.61 (s, 1H), 7.57 (m, 2H), 7.65 (dd, J = 8.88, 2.44 Hz, 1H), 7.78 (dd, J = 7.03, 1.17 Hz, 1H), 7.83 (d, J = 2.34 Hz, 1H), 8.00 (dd, J = 6.05, 3.32 Hz, 1H), 8.09 (d, J = 8.40 Hz, 1H), 8.29 (m, 1H) 8.39 (s, 1H), 8.56 (m, 1H), 8.96 (s, 1H), 11.87 (s, 1H). MS (ESI) (M + H) +422.1. B). N- [2-[[4- (aminofluorenyl) -l_ Hexahydropyridyl] carbonyl] -4-aminophenyl] -1-carbamidine, its corresponding TFA salt (32 mg, 10%). ^ NMRGOOMHz, DMSO-D6) δ 1.25 (m, 4H), 1.61 (s, 2H), 1.74 (m, 3H)? 2.65 (m, 2H), 4.39 101539 • 43- 200539856 (s, 2H), 7. · 38 (d, J = 2.54 Hz, 1H), 7.50 (m, 1H), 7.54 (m, 3H), 7.66 (m, 2H), 7.96 (m, 1H), 8.02 (m, 1H), 8.23 (s , 1H), 10.42 (s, 1H) · MS (ESI) (M + H) + 422.1. Examples 10 and 11 N- [2-[[4- (2-aminoethyl) -1-hexahydropyridine Aryl] carbonyl] -4-aminophenyl] -1-l-carboxamidine and N- [4-chloro-2-[[[2- (1-hexahydropyridyl) ethyl] amino] Isopropyl] phenyl] carboxamide

按照實例1中步驟Α之程序，使用DMF (5毫升）中之5-氣基 莕基羰基)胺基]-苯曱酸(200.0毫克，0.61毫莫耳）、HATU (257.0毫克，0.68毫莫耳）及1-(2·胺基乙基）六氫吡畊（160微升， 1·22毫莫耳）。使產物藉由逆相hplc，使用20-80% CH3CN/H20 純化，然後凍乾，以提供下列兩種二化合物： a) . N-[2-[[4-(2-胺基乙基）小六氫吡畊基]魏基]-4·氣苯基]小莕羧 醯胺，為其相應之TFA鹽（19毫克，6%)。iHNMRQOOMHz， DMSO-D6) 5 2.45 (m，2H)，3.11 (m，6H)，3_22 (s，2H)，3.63 (m，2H)，4.99 (s，2H)，7.41 (d，J=8.20 Hz，1H)，7·55 (m, 3H)，7.66 (dd，J=7.03, 0·98 Hz，1H)， 7.97 (m，3H)，8.04 (d，J=8.01 Hz，1H)，8_23 (dd，J=6.25, 3.32 Hz，1H)，10·64 (s，1H)_ MS (ESI) (M+H)+437.1. b) N-[4-氣基-2-[[[2-(l-六氫吡呼基）乙基]胺基機基]苯基]_1-茶 101539 -44· 200539856 羧醯胺，為其相應之TFA鹽（33毫克，10%)。iHNMRGOOMHz， DMSO-D6) 5 2·44 (m，2H)，3.22 (m，8H)，3.45 (m，2H)，4·86 (s，1H)，7.57 (m，3H)，7.82 (m，2H)，7.99 (m，1H)，8·08 (d, J=7.81 Hz, 1H)，8.31 (s，1H)， 8.54 (s，1H)，8.99 (m，2H)，1L81 (s，1H)· MS (ESI) (M+H)+437.1. 實例12 N-[4-(乙醯胺基）-24[(環己基甲基）胺基]羰基]苯基]-1-莕羧醯胺Follow the procedure of step A in Example 1 using 5-aminofluorenylcarbonyl) amine] -phenylarsinic acid (200.0 mg, 0.61 mmol) in DMF (5 ml), HATU (257.0 mg, 0.68 mmol) Ear) and 1- (2 · aminoethyl) hexahydropyrine (160 µl, 1.22 mmol). The product was purified by reverse phase hplc using 20-80% CH3CN / H20 and then lyophilized to provide the following two compounds: a). N- [2-[[4- (2-aminoethyl) Hexahydropyridyl] Weiji] -4 · Phenyl] carboxamide, its corresponding TFA salt (19 mg, 6%). iHNMRQOOMHz, DMSO-D6) 5 2.45 (m, 2H), 3.11 (m, 6H), 3_22 (s, 2H), 3.63 (m, 2H), 4.99 (s, 2H), 7.41 (d, J = 8.20 Hz , 1H), 7.55 (m, 3H), 7.66 (dd, J = 7.03, 0.98 Hz, 1H), 7.97 (m, 3H), 8.04 (d, J = 8.01 Hz, 1H), 8_23 ( dd, J = 6.25, 3.32 Hz, 1H), 10.64 (s, 1H) _ MS (ESI) (M + H) +437.1. b) N- [4- 气 基 -2-[[[2- (l-hexahydropyridyl) ethyl] aminomethyl] phenyl] _1-tea 101539 -44 · 200539856 Carboxamide, its corresponding TFA salt (33 mg, 10%). iHNMRGOOMHz, DMSO-D6) 5 2.44 (m, 2H), 3.22 (m, 8H), 3.45 (m, 2H), 4.86 (s, 1H), 7.57 (m, 3H), 7.82 (m, 2H), 7.99 (m, 1H), 8.08 (d, J = 7.81 Hz, 1H), 8.31 (s, 1H), 8.54 (s, 1H), 8.99 (m, 2H), 1L81 (s, 1H ) · MS (ESI) (M + H) +437.1. Example 12 N- [4- (Ethylamino) -24 [(cyclohexylmethyl) amino] carbonyl] phenyl] -1-fluorenecarboxamidine amine

步驟Α· N-[4-(乙醯胺基)-2-[[(環己基甲基）胺基]羰基]苯基]小莕 羧醯胺Step A · N- [4- (Ethylamido) -2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] berbene Carboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之5_(乙醯 胺基)-2-[(1-萘基羰基）胺基]-苯甲酸（1.55毫莫耳，關於其製備 可參閱步驟B)、HATU (707.0毫克，1.86毫莫耳）及環己基甲 胺（483微升，3.1毫莫耳）。使產物藉由逆相HPLC，使用20-80% cHsCN/i^o純化，然後凍乾，以提供標題化合物（36毫克， 5%)。1H NMR (400 MHz，DMSO-D6) δ 0.83 (s，2H)，1.07 (s，2H)，1.44 (m，1Η)，1·60 (m，5Η)，2.02 (s，3Η)，2·98 (m，1Η)，7·56 (m，3Η)，7·72 (m，2Η)， 101539 -45- 200539856 7·83 (d，J=2.34 Ηζ，1Η)，7·98 (m，1H)，8.06 (d，J=8.40 Ηζ，1Η)，8·29 (m，1H), 8.35 (d，J=8.79 Hz，1H)，8.67 (t，J=5.76 Hz，1H)，10.05 (s，1H)，11.25 (s，1H). MS (ESI) (M+H)+444.0. 步驟B· 5-(乙醯胺基）-2-[(l-萘基羰基）胺基]-苯甲酸Following the procedure of Step A in Example 1, 5_ (acetamido) -2-[(1-naphthylcarbonyl) amino] -benzoic acid (1.55 millimoles in DMF (5 ml) was used, for its preparation See step B), HATU (707.0 mg, 1.86 mmol) and cyclohexylmethylamine (483 μl, 3.1 mmol). The product was purified by reverse-phase HPLC using 20-80% cHsCN / SiO, and then lyophilized to provide the title compound (36 mg, 5%). 1H NMR (400 MHz, DMSO-D6) δ 0.83 (s, 2H), 1.07 (s, 2H), 1.44 (m, 1Η), 1.60 (m, 5Η), 2.02 (s, 3Η), 2 · 98 (m, 1Η), 7.56 (m, 3Η), 7.72 (m, 2Η), 101539 -45- 200539856 7.83 (d, J = 2.34 Ηζ, 1Η), 7.98 (m, 1H), 8.06 (d, J = 8.40 Ηζ, 1Η), 8.29 (m, 1H), 8.35 (d, J = 8.79 Hz, 1H), 8.67 (t, J = 5.76 Hz, 1H), 10.05 ( s, 1H), 11.25 (s, 1H). MS (ESI) (M + H) +444.0. Step B. 5- (Ethylamino) -2-[(l-naphthylcarbonyl) amino]- benzoic acid

按照實例1中步驟B之程序，使用二氣甲烷（1〇毫升）中之 5-(乙醯胺基）-2-胺基-苯甲酸（300毫克，1.55毫莫耳）、氣化1-莕醯（310微升，1.55毫莫耳）及三乙胺（216微升，1.55毫莫耳）。 將粗製5-(乙醯胺基）-2-[(1_莕基羰基）胺基]-苯甲酸直接用於 步驟A。 實例13 N-[4-胺基-2-[[(環己基甲基）胺基]羰基]苯基]小莕羧醯胺Following the procedure of step B in Example 1, using 5- (acetamido) -2-amino-benzoic acid (300 mg, 1.55 mmol) in digas methane (10 ml), gasify 1- Thorium (310 μl, 1.55 mmol) and triethylamine (216 μl, 1.55 mmol). Crude 5- (acetamido) -2-[(1-fluorenylcarbonyl) amino] -benzoic acid was used directly in Step A. Example 13 N- [4-Amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] berberylcarboxamide

步驟Α· N-[4-胺基-2-[[(環己基甲基）胺基機基]苯基]-1_茶羧醯胺 101539 -46- 200539856Step A · N- [4-Amino-2-[[(cyclohexylmethyl) aminomethyl] phenyl] -1_teacarboxamide 101539 -46- 200539856

將鈀/碳（50毫克，10%等級）添加至得自步驟C之N-[2-[[(環 己基曱基）胺基]羰基]-4-頌基苯基]-1-茶羧醯胺在醋酸乙酯 (30毫升）中之溶液内。將此懸浮液置於帕爾裝置中，並於 氫大氣下振盪3小時(40 psi)。然後，使此懸浮液來到常壓， 並於矽藻土上過濾。使濾液在真空中濃縮。使產物藉由逆 相HPLC，使用20-80% CH3 CN/H2 Ο純化，然後束乾，以提供 標題化合物（36 毫克，1.3%)。1H NMR (400 MHz，DMSO_D6) 5 0.81 (m，2H)，1.08 (m，4H)，L42 (m，1H)，L58 (m，4H)，2·96 (t，J=6.35 Hz，2H)， 4.59 (s，2H)，7.03 (s，1H)，7.15 (s，1H)，7.54 (m，3H)，7·71 (dd，J=7.03, 0.98 Hz，1H)，7.96 (m，1H)，8.03 (d，J=8.40 Hz，1H)，8.25 (m，2H)，8.62 (s，1H)， 11.19 (s，1H). MS (ESI) (M+H)+402.2· 步驟B· 2-[(l-莕基羰基）胺基]-5-硝基-苯甲酸Add palladium / carbon (50 mg, 10% grade) to N- [2-[[(cyclohexylfluorenyl) amino] carbonyl] -4-sonylphenyl] -1-teacarboxylate obtained from Step C A solution of amidine in ethyl acetate (30 ml). This suspension was placed in a Parr apparatus and shaken under a hydrogen atmosphere for 3 hours (40 psi). This suspension was then brought to atmospheric pressure and filtered on diatomaceous earth. The filtrate was concentrated in vacuo. The product was purified by reverse phase HPLC using 20-80% CH3CN / H2O and then dried to provide the title compound (36 mg, 1.3%). 1H NMR (400 MHz, DMSO_D6) 5 0.81 (m, 2H), 1.08 (m, 4H), L42 (m, 1H), L58 (m, 4H), 2.96 (t, J = 6.35 Hz, 2H) , 4.59 (s, 2H), 7.03 (s, 1H), 7.15 (s, 1H), 7.54 (m, 3H), 7.71 (dd, J = 7.03, 0.98 Hz, 1H), 7.96 (m, 1H ), 8.03 (d, J = 8.40 Hz, 1H), 8.25 (m, 2H), 8.62 (s, 1H), 11.19 (s, 1H). MS (ESI) (M + H) + 402.2 · Step B · 2-[(l-fluorenylcarbonyl) amino] -5-nitro-benzoic acid

按照實例1中步驟B之程序，使用二氣曱烷（1〇毫升）中之 5-硝基-2-胺基-苯曱酸（1.0毫克，5.49毫莫耳）、氣化1_莕醜（u 毫升，5.49毫莫耳）及三乙胺（765微升，5.49毫莫耳）。將粗 製2-[(1-莕基羰基）胺基]-5-确基-苯甲酸直接用於步驟C。 101539 • 47- 200539856 步驟C· N-[2-[[(環己基甲基）胺基]幾基]-4-靖基苯基]-1-茶羧醯胺Follow the procedure of Step B in Example 1 using 5-nitro-2-amino-phenylarsinic acid (1.0 mg, 5.49 mmol) in dioxane (10 ml), (U ml, 5.49 mmol) and triethylamine (765 µl, 5.49 mmol). The crude 2-[(1-fluorenylcarbonyl) amino] -5-chloro-benzoic acid was used directly in step C. 101539 • 47- 200539856 Step C · N- [2-[[(Cyclohexylmethyl) amino] Jinyl] -4-Azylphenyl] -1-Tetracarboxamide

按照實例1中步驟A之程序，使用DMF (5毫升）中之2-[(1-莕基羰基）胺基]_5_硝基-苯甲酸(5.49毫莫耳）、HATU (2.3克， 6.05毫莫耳）及環己基甲胺（丨·43毫升，η毫莫耳）。使產物藉 由逆相HPLC，使用20-80% CH3CN/H20純化，然後直接用於 步驟A。 實例14 Ν·[4-氯基·2-[[[(四氫·2Η-哌喃-4-基）甲基]胺基]羰基]苯基]+；!： 羧醯胺Follow the procedure of step A in Example 1 using 2-[(1-fluorenylcarbonyl) amino] -5_nitro-benzoic acid (5.49 mmol) in DMF (5 ml), HATU (2.3 g, 6.05 Mmol) and cyclohexylmethylamine (43 ml, n mmol). The product was purified by reverse-phase HPLC using 20-80% CH3CN / H20 and used directly in step A. Example 14 Ν · [4-chloro · 2-[[[(tetrahydro · 2Η-piperan-4-yl) methyl] amino] carbonyl] phenyl] +;!: Carboxamide

步驟Α· Ν-[4_氯基-2-[[[(四氫-2Η-喊喃-4-基）甲基]胺基]魏基]苯 基]_1_莕羧醯胺 101539 •48· 200539856Step A · Ν- [4-chloro-2--2-[[[(tetrahydro-2Η-sulfan-4-yl) methyl] amino] weiyl] phenyl] _1_ 荇 carboxamidine 101539 • 48 200539856

於室溫下，將4-胺基甲基四氫哌喃（75毫克，〇·66毫莫耳） 添加至6-氣基_2_(1-莕基）-4Η-3，1-苯并噚畊-4-酮（100毫克，0·33 毫莫耳，關於其製備可參閱步驟Β)與二異丙基乙胺（0.5毫 升）在DMF (2毫升）中之溶液内。於2小時後，以Η20 (10毫升） 與乙醚（5毫升）使反應混合物淬滅。收集沉澱物，並在真空 中乾燥，以提供標題化合物（130毫克，93%)。iHNMR(400MHz， CDC13) δ 1.16 (m，2H)，1·62 (m，2H)，1.82 (m，1Η)，3·29 (m，2H)，3.36 (m， 2H)，3.98 (m，2H)，6.30 (brs，1H)，7.46 (m，1H)，7.57 (m，4H)，7.84 (m，1H)， 7.91 (m, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.51 (dd, J=8.0, 1.2 Hz, 1H), 8.87 (dd, J=8.8, 1.2 Hz，1H)，11.49 (brs，1H) ; MS (ESI) (M+H)+423-0· 步驟B· 6-氯基-2-(1_莕基）-4H-3，l·苯并噚畊-4_酮At room temperature, 4-aminomethyltetrahydropiperan (75 mg, 0.66 mol) was added to 6-amino-2- (1-fluorenyl) -4fluorene-3,1-benzo Phenyl-4-one (100 mg, 0.33 mmol) can be prepared by referring to step B) and a solution of diisopropylethylamine (0.5 ml) in DMF (2 ml). After 2 hours, the reaction mixture was quenched with Η20 (10 ml) and diethyl ether (5 ml). The precipitate was collected and dried in vacuo to provide the title compound (130 mg, 93%). iHNMR (400MHz, CDC13) δ 1.16 (m, 2H), 1.62 (m, 2H), 1.82 (m, 1Η), 3.29 (m, 2H), 3.36 (m, 2H), 3.98 (m, 2H), 6.30 (brs, 1H), 7.46 (m, 1H), 7.57 (m, 4H), 7.84 (m, 1H), 7.91 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 8.0, 1.2 Hz, 1H), 8.87 (dd, J = 8.8, 1.2 Hz, 1H), 11.49 (brs, 1H); MS (ESI) (M + H) + 423-0 · Steps B · 6-chloro-2- (1_fluorenyl) -4H-3, l · benzopyrene-4_one

於室溫在0°C下，將CH2C12(2毫升）中之^萘羰基氣（4 〇克， 21毫莫耳）添加至2-胺基5-氣苯甲酸（3·43克，2〇 〇毫莫耳）與 二異丙基乙胺（3毫升）在二氣甲烷（5〇毫升）中之溶液内。將 反應混合物於室溫下攪拌過夜，然後在真空中縮合。使殘 二異丙基乙胺（3 留物溶於無水DMF (30毫升）中，並接著添加二 101539 -49- 200539856 毫升）與HATU(8.4克，22毫莫耳）。於室溫下在攪拌1小時後， 以冷水（100毫升）在〇。(3下使反應淬滅。收集沉殿物，並在真 空中乾燥，以提供標題化合物（6.1克，99%)。MS (ESI) (M+H)+ 308.0. 實例15 N-[4-氣基-2-[[(環丙基甲基）胺基]幾基]苯基]-1-審竣醯胺Naphthylcarbonyl gas (40 g, 21 mmol) in CH2C12 (2 ml) was added to 2-amino5-gas benzoic acid (3.43 g, 2.0 at room temperature at 0 ° C). 0 mmol) and a solution of diisopropylethylamine (3 ml) in methane gas (50 ml). The reaction mixture was stirred at room temperature overnight and then condensed in vacuo. The residual diisopropylethylamine (3 retentate was dissolved in anhydrous DMF (30 ml), and then di 101539 -49- 200539856 ml) was added with HATU (8.4 g, 22 mmol). After stirring at room temperature for 1 hour, cold water (100 ml) was used. (The reaction was quenched at 3 times. The sink was collected and dried in vacuo to provide the title compound (6.1 g, 99%). MS (ESI) (M + H) + 308.0. Example 15 N- [4- 2-([(Cyclopropylmethyl) amino] amino] phenyl] -1-phenylamine

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇.5毫 升）、6-氣基-2_(1-莕基）-4Η-3，1-苯并4畊-4-酮（100毫克，〇·33毫 莫耳）及環丙基甲胺（71毫克，1.0毫莫耳），提供標題化合物 (64 毫克，53%)。111丽11(400]^出，€〇(：13)(5 0.24-0.27(111，211)，0.55-0.59 (m，2Η)，0.98-1.08 (m，1Η)，3.22 (dd，J=7.23，5.27 Hz, 2Η)，6.31-6.36 (br· s” 1H)，7.51-7.59 (m，5H)，7.85 (dd，J=7.22, 1.17 Hz，1H)，7·89 (m，1H)， 7.88-7.98 (d, J=8.20 Hz, 1H), 8.52 (m, 1H), 8.88 (d, J=8.98 Hz, 1H), 11.58 (s，1H); MS (ESI) (M+H)+ 378.9 ;對 C2 2 9 C1N2 02 + 0· 1 H2 O 之分析 計算值：C，69.42 ; H，5.08 ; N，7·36·實測值：C，69.42 ; H，5.13 ; N，7_36· 實例16 N-[4-氯基-2-[(環己胺基）羰基]苯基]小苯羧醯胺 101539 -50- 200539856Following the procedure as in step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2_ (1-fluorenyl) -4fluorene-3,1-benzo4 Ketones (100 mg, 0.33 mmol) and cyclopropylmethylamine (71 mg, 1.0 mmol) provided the title compound (64 mg, 53%). 111 Li 11 (400) ^ out, € 〇 (: 13) (5 0.24-0.27 (111,211), 0.55-0.59 (m, 2Η), 0.98-1.08 (m, 1Η), 3.22 (dd, J = 7.23, 5.27 Hz, 2Η), 6.31-6.36 (br · s ”1H), 7.51-7.59 (m, 5H), 7.85 (dd, J = 7.22, 1.17 Hz, 1H), 7.89 (m, 1H) , 7.88-7.98 (d, J = 8.20 Hz, 1H), 8.52 (m, 1H), 8.88 (d, J = 8.98 Hz, 1H), 11.58 (s, 1H); MS (ESI) (M + H) + 378.9; Analytical calculated value for C2 2 9 C1N2 02 + 0 · 1 H2 O: C, 69.42; H, 5.08; N, 7.36. Found: C, 69.42; H, 5.13; N, 7_36. Example 16 N- [4-Chloro-2-[(cyclohexylamino) carbonyl] phenyl] benzylcarboxamide 101539 -50- 200539856

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基·2-(1·奈基）-4Η-3，1-苯弁**亏呼-4-嗣（100毫克，0.33毫 莫耳）及環己胺（99毫克，L0毫莫耳），提供標題化合物（1〇3 毫克，79%)。1H NMR (400 MHz, CDC13) 3 U5-1.27 (m，3H)，1.31-1.42 (m, 2H), 1.58-1.67 (m, 1H), 1.72-1.77 (m, 2H), 1.95-1.99 (m, 2H), 3.81-3.90 (m，1H)，6.07 (d，J=7.42 Hz, 1H)，7.45 (d，J=2.54 Hz，1H)，7.50-7.59 (m，4H)， 7.84 (dd, J=7.0351.17 Hz, 1H), 7.88-7.90 (m, 1H), 7.97 (d, 1=8.40 Hz, 1H), 8.51 (dd, 1=8.01, 1.17 Hz, 1H)5 8.86 (d5 J=8.79 Hz, 1H), 11.55-11.59 (br. s., 1H); MS(ESI)(M+H)+407.0;對(：241123 0^202 + 0.1 1120 之分析計 算值：C，70·53 ; H，5·72 ; N，6·85·實測值：C，70.69; H，5·86; N，6·79· 實例17Following the procedure as in step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino · 2- (1 · naphthyl) -4 ， -3,1-benzene 弁 ** 亏 -4-4 -Hydrazone (100 mg, 0.33 mmol) and cyclohexylamine (99 mg, L0 mmol) to provide the title compound (103 mg, 79%). 1H NMR (400 MHz, CDC13) 3 U5-1.27 (m, 3H), 1.31-1.42 (m, 2H), 1.58-1.67 (m, 1H), 1.72-1.77 (m, 2H), 1.95-1.99 (m , 2H), 3.81-3.90 (m, 1H), 6.07 (d, J = 7.42 Hz, 1H), 7.45 (d, J = 2.54 Hz, 1H), 7.50-7.59 (m, 4H), 7.84 (dd, J = 7.0351.17 Hz, 1H), 7.88-7.90 (m, 1H), 7.97 (d, 1 = 8.40 Hz, 1H), 8.51 (dd, 1 = 8.01, 1.17 Hz, 1H) 5 8.86 (d5 J = 8.79 Hz, 1H), 11.55-11.59 (br. S., 1H); MS (ESI) (M + H) +407.0; Analytical calculated value for (: 241123 0 ^ 202 + 0.1 1120: C, 70 · 53 H, 5.72; N, 6.85. Found: C, 70.69; H, 5.86; N, 6.79. Example 17

N-[4-氣基-2-[[(環丁基甲基）胺基]羰基]苯基]-l-莕羧醯胺N- [4-Gasyl-2-[[(cyclobutylmethyl) amino] carbonyl] phenyl] -1-l-carboxamidine

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇.5毫 升）、6-氣基-2-(1-莕基)-4Η-3，1·苯并哼畊-4-酮（1〇〇毫克，0.33毫 莫耳）及環丁基甲胺（85毫克，1.0毫莫耳），提供標題化合物 101539 -51 - 200539856 (107 毫克，85%)。iHNMRGOOMHz'DCIJS 1.66-1.76(m，2H)， 1.85-1.96 (m，2H)，2.05-2.12 (m，2H)，2.50-2.58 (m，1H)，3.39 (dd，J=7.32， 5.76 Hz，2H)，6.15-6.22 (m，1H)，7.45 (d，J=2.54 Hz，1H)，7·51-7_59 (m，4H)， 7.84 (dd，J=7.23, 1.17 Hz, 1H)，7.88-7.90 (m，1H)，7.97 (d，J=8.40 Hz，1H)， 8.52 (dd，J=8_01，1.17 Hz，1H)，8.87 (d，J=8.98 Hz，1H)，11.55 (br· s·，1H); MS (ESI) (M+H)+ 393_0;對 C2 3 H2! C1N2 02 + 0·1 H2 0 之分析計算值： C，69.99 ; H，5.41; N，7.10.實測值：C，70.09 ; Η，5·31; N，7.02. 實例18 N-[4-氣基-2-[[(環庚基甲基）胺基]羰基]苯基]-1-莕羧醢胺Following step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1. -Ketones (100 mg, 0.33 mmol) and cyclobutylmethylamine (85 mg, 1.0 mmol) provide the title compound 101539 -51-200539856 (107 mg, 85%). iHNMRGOOMHz'DCIJS 1.66-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05-2.12 (m, 2H), 2.50-2.58 (m, 1H), 3.39 (dd, J = 7.32, 5.76 Hz, 2H), 6.15-6.22 (m, 1H), 7.45 (d, J = 2.54 Hz, 1H), 7.51-7_59 (m, 4H), 7.84 (dd, J = 7.23, 1.17 Hz, 1H), 7.88 -7.90 (m, 1H), 7.97 (d, J = 8.40 Hz, 1H), 8.52 (dd, J = 8_01, 1.17 Hz, 1H), 8.87 (d, J = 8.98 Hz, 1H), 11.55 (br · s · ， 1H); MS (ESI) (M + H) + 393_0; Analytical calculated value for C2 3 H2! C1N2 02 + 0 · 1 H2 0: C, 69.99; H, 5.41; N, 7.10. Measured value : C, 70.09; Hf, 5.31; N, 7.02. Example 18 N- [4-Gas-2-[[(cycloheptylmethyl) amino] carbonyl] phenyl] -1-fluorenecarboxamidine amine

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1·莕基)-4Η-3，1_苯并呤畊·4-酮（100毫克，0.33毫 莫耳）及環庚烷甲胺（127毫克，1.0毫莫耳），提供標題化合 物（128 毫克，92%)。iHNMRGOOMHACDC^) 5 1.17-1.25(m，2H)， I. 38-1.78 (m，1H)，3.22 (t，J=6.25 Hz，2H)，6.7-6.30 (m，1H)，7·46 (d，J=2.54 Hz5 1H)5 7.52-7.59 (m, 4H), 7.83 (dd5 J=7.035 1.17 Hz, 1H)5 7.88-7.90 (m, 1H)，7.97 (d，J=8.40 Hz，1H)，8.50-8.52 (m，1H)，8·87 (d，J=8.98 Hz，1H)， II. 53 (br_s.，lH); MS (ESI) (M+H)+435.0;對 C26H27C1N202+0.1 H20 之分析計算值：C，71.50 ; H，6·28 ; N，6.41.實測值：C，71.39 ; H，6·25 ; N，6.36. 101539 -52- 200539856 實例19 N-[4-氯基-2-[[[(2-羥基環己基）甲基]胺基]羰基]苯基]小莕羧醯胺According to the method in step A in Example 14, diisopropylethylamine (0.5 ml), 6-amino-2- (1 · fluorenyl) -41-3,1_benzopyrine, 4-ketone were used. (100 mg, 0.33 mmol) and cycloheptanemethylamine (127 mg, 1.0 mmol) provided the title compound (128 mg, 92%). iHNMRGOOMHACDC ^) 5 1.17-1.25 (m, 2H), I. 38-1.78 (m, 1H), 3.22 (t, J = 6.25 Hz, 2H), 6.7-6.30 (m, 1H), 7.46 (d , J = 2.54 Hz5 1H) 5 7.52-7.59 (m, 4H), 7.83 (dd5 J = 7.035 1.17 Hz, 1H) 5 7.88-7.90 (m, 1H), 7.97 (d, J = 8.40 Hz, 1H), 8.50-8.52 (m, 1H), 8.87 (d, J = 8.98 Hz, 1H), II. 53 (br_s., LH); MS (ESI) (M + H) +435.0; for C26H27C1N202 + 0.1 H20 Analytical calculated values: C, 71.50; H, 6.28; N, 6.41. Found: C, 71.39; H, 6.25; N, 6.36. 101539 -52- 200539856 Example 19 N- [4-chloro group -2-[[[(2-hydroxycyclohexyl) methyl] amino] carbonyl] phenyl] berberylcarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基_2-(1-莕基)-4Η-3，1-苯并嘮畊-4-酮（100毫克，0.33毫 莫耳）及2-(胺基甲基)-環己醇（129毫克，1.0毫莫耳），提供標 題化合物（80 毫克，57%)。iHNMRGOOMHz’CDCDS 1.27-1.36 (m, 1H)51.46-1.67 (m, 8H), L81-1.91 (m5 1H), 3.39 (d5 5.86 Hz, 2H)5 6.67-6.70 (m, 1H), 7.51-7.57 (m, 4H), 7.82 (dd, J=7.13, 1.27 Hz, 1H), 7.87-7.90 (m, 1H), 7.95-7.98 (m, 1H), 8.50-8.52 (m, 1H), 8.86-8.89 (m, 1H), 11.54- 11.58 (brs，lH); MS (ESI) (M+H)+473.0;對 C25H25C1N203 + 0.1 H20 + 0.1013〇^[之分析計算值：（：，68.22;11，5.84;]^，6.34.實測值： C, 68.28 ； H, 5.75 ； N, 6.36. 實例20 Ν-[4·氣基-2-[(3-羥基_1-六氫吡啶基）羰基]苯基]+莕羧醯胺Following step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2-(1-fluorenyl) -4fluorene-3,1-benzopyrene-4-one (100 mg, 0.33 mmol) and 2- (aminomethyl) -cyclohexanol (129 mg, 1.0 mmol) provided the title compound (80 mg, 57%). iHNMRGOOMHz'CDCDS 1.27-1.36 (m, 1H) 51.46-1.67 (m, 8H), L81-1.91 (m5 1H), 3.39 (d5 5.86 Hz, 2H) 5 6.67-6.70 (m, 1H), 7.51-7.57 ( m, 4H), 7.82 (dd, J = 7.13, 1.27 Hz, 1H), 7.87-7.90 (m, 1H), 7.95-7.98 (m, 1H), 8.50-8.52 (m, 1H), 8.86-8.89 ( m, 1H), 11.54- 11.58 (brs, lH); MS (ESI) (M + H) +473.0; Analytical calculation for C25H25C1N203 + 0.1 H20 + 0.1013〇 ^ [: (:, 68.22; 11, 5.84; ] ^, 6.34. Found: C, 68.28; H, 5.75; N, 6.36. Example 20 N- [4 · Gas-2-[(3-hydroxy_1-hexahydropyridyl) carbonyl] phenyl] + Carboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇·5毫 101539 •53· 200539856 升）、6-氣基-2-(1-莕基）-4Η-3，1-苯并，畊-4-酮（100毫克，0.33毫 莫耳）及3-羥基六氫吡啶（101毫克，1.0毫莫耳），提供標題化 合物（104 毫克，79%)。iHNMRGOOMHACDCld 5 1.43-1.55 (m， 1H)，1.63-1.93 (m，4H)，1.99-2.15 (m，1H)，3·31-3·54 (m5 2H)，3·76·3·86 (m， 1H)，7.19-7.25 (m，1H)，7.31-7.41 (m，1H)，7.45-7.51 (m，2H)，7.52-7.58 (m， 3H)，7.73 (d，J=6.64 Hz，1H)，7.87-7.89 (m，1H)，7.95 (d5 J=8.40 Hz，1H)， 8.42 (d，J=7-62 Hz，1H)，9.29-7.40 (br. s.，1H) ; MS (ESI) (M+H)+409.0 ; 對（：231121(：11^2〇3 + 0.1112〇之分析計算值：<：，67.27;11，5.20; N，6·82·實測值：C，67.18 ; H，5.20 ; N，6.75. 實例21 N-[4-氣基-2-[[3-(羥甲基）小六氫吡啶基]羰基]苯基]小莕羧醯胺According to the method as in step A in Example 14, diisopropylethylamine (0.5 mmol 101539 • 53 · 200539856 liter), 6-amino-2- (1-fluorenyl) -4fluorene-3,1- Benzo, phen-4-one (100 mg, 0.33 mmol) and 3-hydroxyhexahydropyridine (101 mg, 1.0 mmol) provided the title compound (104 mg, 79%). iHNMRGOOMHACDCld 5 1.43-1.55 (m, 1H), 1.63-1.93 (m, 4H), 1.99-2.15 (m, 1H), 3.3-31-3 · 54 (m5 2H), 3.76 · 3 · 86 (m , 1H), 7.19-7.25 (m, 1H), 7.31-7.41 (m, 1H), 7.45-7.51 (m, 2H), 7.52-7.58 (m, 3H), 7.73 (d, J = 6.64 Hz, 1H ), 7.87-7.89 (m, 1H), 7.95 (d5 J = 8.40 Hz, 1H), 8.42 (d, J = 7-62 Hz, 1H), 9.29-7.40 (br. S., 1H); MS ( ESI) (M + H) +409.0; Analytical calculated value for (: 231121 (: 11 ^ 2 03 + 0.1112): <:,67.27; 11, 5.20; N, 6.82. Found: C, 67.18; H, 5.20; N, 6.75. Example 21 N- [4-Amino-2-[[3- (hydroxymethyl) small hexahydropyridyl] carbonyl] phenyl] berberylcarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1-莕基)-4Η-3，1-苯并崎畊-4-酮（100毫克，0.33毫 莫耳）及3-六氫吡啶甲醇（115毫克，1.0毫莫耳），提供標題化 合物（124 毫克，92%)。WNMR(400MHz，CDC13) (5 1.27-1.87(m， 8H)，3.11-3.23 (m，1H)，3.44-3.51 (m，2H)，7.25 (d，J=2_54 Hz，1H)，7.46 (dd， J=8.79,2.34 Hz，1H)，7.44-7.60 (m，4H)，7·76 (dd，J=7.13, 0.88 Hz，1H)，7.89 -7.92 (m，1H)，7.98 (d，J=8.20 Hz，1H)，8.46-8.48 (br s，1H)，9.41 (br. s” 1H); MS(ESI)(M+H)+423.0 ;對 C24H23C1N203 + 0.1 H20 之分析計算 101539 -54- 200539856 值：C，67.87 ; Η，5·51; Ν，6·60·實測值：C，67.85; Η，5·47; N，6.51. 實例22 N-[4-氣基-2-[(六氫-1H—氮七圜烯-μ基）羰基]苯基；^莕羧醯胺Following step A in Example 14 using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1-benzozaki-4 (100 mg, 0.33 mmol) and 3-hexahydropyridine methanol (115 mg, 1.0 mmol) provided the title compound (124 mg, 92%). WNMR (400MHz, CDC13) (5 1.27-1.87 (m, 8H), 3.11-3.23 (m, 1H), 3.44-3.51 (m, 2H), 7.25 (d, J = 2_54 Hz, 1H), 7.46 (dd , J = 8.79, 2.34 Hz, 1H), 7.44-7.60 (m, 4H), 7.76 (dd, J = 7.13, 0.88 Hz, 1H), 7.89 -7.92 (m, 1H), 7.98 (d, J = 8.20 Hz, 1H), 8.46-8.48 (br s, 1H), 9.41 (br. S ”1H); MS (ESI) (M + H) +423.0; Analysis and calculation for C24H23C1N203 + 0.1 H20 101539 -54- 200539856 Value: C, 67.87; Tritium, 5.51; N, 6.60. Found: C, 67.85; Tritium, 5.47; N, 6.51. Example 22 N- [4- 气 基 -2-[( Hexahydro-1H-azaheptaene-μyl) carbonyl] phenyl;

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇.5毫 升）、6·氯基_2_(1_莕基）-4Η-3，1-苯并，号哨-4-酮（100毫克，0.33毫 莫耳）及六氫-1H-—氮七圜烯（99毫克，1.0毫莫耳），提供標 題化合物（61 毫克，47%)。iHNMRGOOMH^CDCL) (5 1.54-1.58 (m5 4H), 1.64-1.78 (m, 4H), 3.49 (t, J=6.15 Hz, 2H), 3.59-3.62 (m, 2H), 121 (d? J=2.15 Hz, 1H)5 7.46 (dd5 J=8.79, 2.34 Hz, 1H), 7.45-7.59 (m, 3H), 7.74 (dd, J=7.13, 1.27 Hz, 1H), 7.89-7.91 (m, 1H), 7.98 (d, J=8.20 Hz, 1H)5 8.44-8.48 (m, 2H), 9.20 (br s, 1H) ； MS (ESI) (M+H)+407.0 ； 對 C24H23ClN2O2+0.1CH3OH 之分析計算值：C，70.58; H，5.75; N，6.83.實測值：C，70.66 ; H，5.50 ; N，6.74. 實例23 N-[4-氣基-2-(1-四氫吡咯基羰基）苯基]小莕羧醯胺Following step A in Example 14, using diisopropylethylamine (0.5 ml), 6.chloro-2- (1_fluorenyl) -4fluorene-3,1-benzo, whistle-4 -Ketone (100 mg, 0.33 mmol) and hexahydro-1H-azaheptaene (99 mg, 1.0 mmol) provide the title compound (61 mg, 47%). iHNMRGOOMH ^ CDCL) (5 1.54-1.58 (m5 4H), 1.64-1.78 (m, 4H), 3.49 (t, J = 6.15 Hz, 2H), 3.59-3.62 (m, 2H), 121 (d? J = 2.15 Hz, 1H) 5 7.46 (dd5 J = 8.79, 2.34 Hz, 1H), 7.45-7.59 (m, 3H), 7.74 (dd, J = 7.13, 1.27 Hz, 1H), 7.89-7.91 (m, 1H) , 7.98 (d, J = 8.20 Hz, 1H) 5 8.44-8.48 (m, 2H), 9.20 (br s, 1H); MS (ESI) (M + H) +407.0; Analysis and calculation of C24H23ClN2O2 + 0.1CH3OH Value: C, 70.58; H, 5.75; N, 6.83. Found: C, 70.66; H, 5.50; N, 6.74. Example 23 N- [4-Gas-2- (1-tetrahydropyrrolylcarbonyl) Phenyl] carboxamide

101539 -55 200539856 按照如實例14中步驟A之方法，使用二異丙基乙胺（〇·5毫 升）、6-氯基_2·(1-莕基）-4Η-3，1-苯并$畊-4-酮（100毫克，〇·33毫 莫耳）及四氫吡咯（71毫克，1.0毫莫耳），提供標題化合物（1〇4101539 -55 200539856 Following the method of step A in Example 14, using diisopropylethylamine (0.5 ml), 6-chloro-2- (1-fluorenyl) -4fluorene-3,1-benzo Ghen-4-one (100 mg, 0.33 mmol) and tetrahydropyrrole (71 mg, 1.0 mmol) provide the title compound (104

毫克，86%)。1H NMR (400 MHz，CDC13) 5 1.86-1.99 (m，4Η)，3.54-3.61 (m，4H), 7·40 (d，J=2.34 Hz，1H)，7_46 (dd，J=8.89, 2·44 Hz，1H)，7.49-7.59 (m，3H)，7·81 (dd，J=7.03，1.17 Hz，1H)，7.88-7.91 (m，1H)，7.97 (d，J=8.40 Hz, 1H)，8.51-8.53 (m，1H)，8_59 (d，J=8.98 Hz，1H)，10.15_10.22 (br s，1H); MS (ESI) (M+H)+ 379.0;對 C2 29 C1N2 02 + 0.2 H2 O 之分析計算值： C，69.09; Η，5·11; Ν，7·32·實測值·· C，69.16; Η，5·02; Ν，7·27· 實例24 Ν-[4-氣基-2-[[(2-羥基環己基）胺基]羰基]苯基]-1-莕羧醯胺Mg, 86%). 1H NMR (400 MHz, CDC13) 5 1.86-1.99 (m, 4Η), 3.54-3.61 (m, 4H), 7.40 (d, J = 2.34 Hz, 1H), 7_46 (dd, J = 8.89, 2 · 44 Hz, 1H), 7.49-7.59 (m, 3H), 7.81 (dd, J = 7.03, 1.17 Hz, 1H), 7.88-7.91 (m, 1H), 7.97 (d, J = 8.40 Hz, 1H), 8.51-8.53 (m, 1H), 8_59 (d, J = 8.98 Hz, 1H), 10.15_10.22 (br s, 1H); MS (ESI) (M + H) + 379.0; for C2 29 Analytical calculated values for C1N2 02 + 0.2 H2 O: C, 69.09; Η, 5. · 11; Ν, 7.32 · Measured values ·, C, 69.16; Η, 5.02; Ν, 7.27 · Example 24 Ν -[4-Amino-2-[[(2-hydroxycyclohexyl) amino] carbonyl] phenyl] -1-carbamidine

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1·莕基)-4Η-3，1-苯并嘮畊斗酮（150毫克，0.49毫 莫耳）及2-胺基環己醇（115毫克，1.0毫莫耳），提供標題化合 物（166 毫克，80%)。iHNMRGOOMHz’CDCb) 5 1.62(m，8H)，4.01 (m，2H)，6.64 (m，1H)，7.54 (m，5H)，7.84 (dd，J=7.2, 1.2 Hz，1H)，7.89 (d， 8.0 Hz? 1H), 7.97 (d, J=8.4 Hz, 1H)3 8.51 (d5 J=8.0 Hz, 1H), 8.87 (d, J=8.4 Hz，1H)，11.61 (brs，1H) ; MS (ESI) (M+H)+423.1. 101539 -56- 200539856 實例25 N-[4-氣基-2-[[[2-(l，3-二氧伍圜-2-基）乙基]胺基]羰基]苯基]—μ萘 羧醯胺According to the method of step A in Example 14, diisopropylethylamine (0.5 ml), 6-amino-2- (1 · fluorenyl) -4, -3,1-benzopyrene, ketone (150 (Mg, 0.49 mmol) and 2-aminocyclohexanol (115 mg, 1.0 mmol) to provide the title compound (166 mg, 80%). iHNMRGOOMHz'CDCb) 5 1.62 (m, 8H), 4.01 (m, 2H), 6.64 (m, 1H), 7.54 (m, 5H), 7.84 (dd, J = 7.2, 1.2 Hz, 1H), 7.89 (d , 8.0 Hz? 1H), 7.97 (d, J = 8.4 Hz, 1H) 3 8.51 (d5 J = 8.0 Hz, 1H), 8.87 (d, J = 8.4 Hz, 1H), 11.61 (brs, 1H); MS (ESI) (M + H) +423.1. 101539 -56- 200539856 Example 25 N- [4-Amino-2-[[[2- (l, 3-dioxol-2-yl) ethyl] Amine] carbonyl] phenyl] -μnaphthylcarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1•萘基）-4Η-3，1-苯并巧畊-4-酮（100毫克，0.33毫 莫耳）及2-(2-胺基乙基）-1，3-二氧伍圜（79毫克，0.66毫莫耳）， 提供標題化合物（131 毫克，94%)。iHNMRGOOMHz’CDClJd 2.00 (m，2H)，3·55 (m，2H)，3.92 (m，2H)，4.04 (m，2H)，5.00 (m，1H)，7.08 (brs, 1H), 7.47 (m, 1H), 7.53 (m, 4H), 7.88 (m, 2H), 7.97 (d, J=8.4 Hz, 1H), 8·52 (d，J=8.0 Hz，1H)，8.89 (d，J=9.2 Hz，1H)，11.72 (brs，1H); MS (ESI) (M+H)+425.1. 實例26 N-[4-氣基-2-[[[l-(羥甲基）環戊基]胺基]羰基；I苯基]小莕羧醯胺 〇Following step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2- (1naphthyl) -4'-3,1-benzoquinone-4-one (100 mg, 0.33 mmol) and 2- (2-aminoethyl) -1,3-dioxolane (79 mg, 0.66 mmol) provided the title compound (131 mg, 94%). iHNMRGOOMHz'CDClJd 2.00 (m, 2H), 3.55 (m, 2H), 3.92 (m, 2H), 4.04 (m, 2H), 5.00 (m, 1H), 7.08 (brs, 1H), 7.47 (m , 1H), 7.53 (m, 4H), 7.88 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 9.2 Hz, 1H), 11.72 (brs, 1H); MS (ESI) (M + H) +425.1. Example 26 N- [4-Airyl-2-[[[l- (hydroxymethyl) cyclopentyl ] Amine] carbonyl; Iphenyl] berberylcarboxamide.

0H 〇0H 〇

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇 5毫 升）、6_氣基-2-(1-笨基)·4Η-3，1-苯并噚畊-4-酮（100毫克，0.33毫 101539 -57- 200539856 莫耳）及1-胺基小環戊烷甲醇（78毫克，0.66毫莫耳），提供標 題化合物（75 毫克，54%)。iHNMRGOOMi^CDCldS 1.65(m， 2H)，1·78 (m，2H)，1·88 (m，4H)，3·37 (t，J=5.2 Hz，1H)，3·68 (d，J=5.2 Hz， 2H)，6.26 (brs，1H)，7.41 (m，1H)，7.50 (m，4H)，7_78 (dd，J=7.2, 1.2 Hz，1H)， 7.86 (m，1H)，7.95 (d，J=8.4 Hz，1H)，8.47 (d，J=8.0 Hz, 1H)，8.78 (d，J=9.2 Hz，1H)，11.18 (brs，1H) ; MS (ESI) (M+H)+423.1. 實例27 N-[4-氯基-2-[(3-羥基-1-四氫吡咯基）羰基]苯基]-i-莕羧醯胺Following the procedure as in step A in Example 14, using diisopropylethylamine (05 ml), 6-amino-2- (1-benzyl) · 4Η-3,1-benzopyrene-4- Ketones (100 mg, 0.33 mmol 101539 -57- 200539856 mole) and 1-amino small cyclopentanemethanol (78 mg, 0.66 mmol) provide the title compound (75 mg, 54%). iHNMRGOOMi ^ CDCldS 1.65 (m, 2H), 1.78 (m, 2H), 1.88 (m, 4H), 3.37 (t, J = 5.2 Hz, 1H), 3.68 (d, J = 5.2 Hz, 2H), 6.26 (brs, 1H), 7.41 (m, 1H), 7.50 (m, 4H), 7_78 (dd, J = 7.2, 1.2 Hz, 1H), 7.86 (m, 1H), 7.95 ( d, J = 8.4 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.78 (d, J = 9.2 Hz, 1H), 11.18 (brs, 1H); MS (ESI) (M + H) +423.1. Example 27 N- [4-Chloro-2-[(3-hydroxy-1-tetrahydropyrrolyl) carbonyl] phenyl] -i-fluorenecarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇·5毫 升）、6-氣基-2-(1·莕基）-4Η·3，1-苯并吟畊-4-酮（100毫克，〇·33毫 莫耳）及3_四氫吡咯醇（53毫克，0.66毫莫耳），提供標題化合 物（45 毫克，35%)。iHNMRGOOMHz’CDCD^l.OtHmJH)，]^ # (m5 4H), 3.84 (m, 1H), 4.46-4.56 (m, 1H)5 7.50 (m, 5H), 7.78 (m, 1H), 7.895 (d，J=7.6 Hz，1H)，7.97 (d，J=7.6 Hz，1H)，8.28-8.48 (m，2H)，9.81-10.03 (m， 1H); MS (ESI) (M+H)+395.0. 實例28 N-[4-氯基-2-[[2-(2-甲氧苯基)-1-四氫吡咯基]羰基]苯基莕羧 101539 -58- 200539856According to the method in step A of Example 14, diisopropylethylamine (0.5 ml), 6-amino-2- (1 · fluorenyl) -4, 3,1-benzoingenol-4 were used. -Ketone (100 mg, 0.33 mmol) and 3-tetrahydropyrrolol (53 mg, 0.66 mmol) to provide the title compound (45 mg, 35%). iHNMRGOOMHz'CDCD ^ l.OtHmJH),] ^ # (m5 4H), 3.84 (m, 1H), 4.46-4.56 (m, 1H) 5 7.50 (m, 5H), 7.78 (m, 1H), 7.895 (d , J = 7.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.28-8.48 (m, 2H), 9.81-10.03 (m, 1H); MS (ESI) (M + H) +395.0 Example 28 N- [4-Chloro-2-[[2- (2-methoxyphenyl) -1-tetrahydropyrrolyl] carbonyl] phenylfluorenylcarboxyl 101539 -58- 200539856

知:照如實例14中步驟A之方法，使用二異丙基乙胺（〇·5毫 升）、6-氣基-2-(1-萘基)_4Η-3，1-苯并吟畊_4_酮（100毫克，〇·33毫 莫耳）及2-(2•甲氧苯基）-四氫吡咯（ι17毫克，〇·66毫莫耳），以 提供標題化合物（52 毫克，33%)。1H NMR (400 MHz，CDC13 ) 5 1.87 (m，3H)，2.24 (m，1H)，3·00 (m，1H)，3·66-3·83 (m，3H)，3·83 (m，1H)， 5·30 (m，1H)，6.67-8.00 (m，12H)，8.52 (m，2H)，9·68-10·04 (m，1H); MS (ESI) (M+H)+485.0. 實例29 N-[4-氣基-2_[[(1，3-二氧伍圜-2-基甲基）胺基]羰基]苯基]莕羧Known: As in step A in Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2- (1-naphthyl) _4_-3,1-benzopyrene_ 4-ketone (100 mg, 0.33 mmol) and 2- (2 • methoxyphenyl) -tetrahydropyrrole (17 mg, 0.66 mmol) to provide the title compound (52 mg, 33 %). 1H NMR (400 MHz, CDC13) 5 1.87 (m, 3H), 2.24 (m, 1H), 3.00 (m, 1H), 3.66-3 · 83 (m, 3H), 3.83 (m , 1H), 5.30 (m, 1H), 6.67-8.00 (m, 12H), 8.52 (m, 2H), 9.68-10 · 04 (m, 1H); MS (ESI) (M + H ) +485.0. Example 29 N- [4-Amino-2 _ [[(1,3-dioxo-2-ylmethyl) amino] carbonyl] phenyl] fluorenecarboxy

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、6-氯基-2-(1-莕基)-4Η-3，1-苯并噚畊·4-酮（100毫克，0.33毫 莫耳）及1，3-二氧伍圜-2-甲胺（68毫克，0.66毫莫耳），提供標 題化合物（98 毫克，72%)。1H NMR (400 MHz，CDC13 ) 5 3.61 (m， 2H)，3.88 (m，2H)，3·98 (m，2H)，4_98 (t，J=3.6 Hz，1H)，6.39 (brs，1H)，7·46 101539 -59- 200539856 (s，1Η)，7·50 (m，4H)，7.83 (dd，J=7.2, 1.2 Hz，1H)，7.85 (d，J=9.2 Hz，1H)， 7.94 (d，J=8.4 Hz，1H)，8.48 (d，J=8.4 Hz，1H)，8.86 (d，J=8.8 Hz，1H)，11.50 (brs，1H) ; MS (ESI) (M+H)+411.1. 實例30 N-[4-氣基-2·[[(四氫_2H-哌喃-4-基）胺基]羰基]苯基]-1-莕羧醯胺Following the method of step A in Example 14, using diisopropylethylamine (0.5 ml), 6-chloro-2- (1-fluorenyl) -4fluorene-3,1-benzopyrene · 4-one (100 mg, 0.33 mmol) and 1,3-dioxo-2-methylamine (68 mg, 0.66 mmol) provided the title compound (98 mg, 72%). 1H NMR (400 MHz, CDC13) 5 3.61 (m, 2H), 3.88 (m, 2H), 3.98 (m, 2H), 4_98 (t, J = 3.6 Hz, 1H), 6.39 (brs, 1H) , 7.46 101539 -59- 200539856 (s, 1Η), 7.50 (m, 4H), 7.83 (dd, J = 7.2, 1.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 8.8 Hz, 1H), 11.50 (brs, 1H); MS (ESI) (M + H) +411.1. Example 30 N- [4-Amino-2 · [[(tetrahydro_2H-piperan-4-yl) amino] carbonyl] phenyl] -1-carboxamidine

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1-莕基)-4Η-3，1-苯并嘮畊-4-酮（100毫克，0.33毫 莫耳）及4_胺基四氫喊喃（67毫克，0.66毫莫耳），提供標題化 合物（116 毫克，86%)。iHNMRGOOMHACDCb) 5 1.59(m，2H)， 1·94 (m，2H)，3·47 (dd，J=11.6, 9.6 Hz，2H)，3.98 (m，2H)，4·12 (m，1H)，6·04 (d，J=7.6 Hz，1H)，7·47 (m，1H)，7.56 (m，4H)，7·84 (dd，J=7.6, 1.2 Hz，1H)， 7.90 (m，1H)，7.98 (d，J=8.4 Hz，1H)，8.51 (d，J=8.4 Hz，1H)，8.88 (d，J=8.8 Hz, 1H)，11.51 (brs，1H) ; MS (ESI) (M+H)+409.0. 實例31 N-[4_氯基-2-[[〇(四氫-2H-哌喃-4-基）乙基]胺基]羰基]苯基]-1- 莕羧醯胺Following step A in Example 14 using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1-benzopyrene-4-one (100 mg, 0.33 mmol) and 4-aminotetrahydrofuran (67 mg, 0.66 mmol) provided the title compound (116 mg, 86%). iHNMRGOOMHACDCb) 5 1.59 (m, 2H), 1.94 (m, 2H), 3.47 (dd, J = 11.6, 9.6 Hz, 2H), 3.98 (m, 2H), 4.12 (m, 1H) , 6.04 (d, J = 7.6 Hz, 1H), 7.47 (m, 1H), 7.56 (m, 4H), 7.84 (dd, J = 7.6, 1.2 Hz, 1H), 7.90 (m , 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.88 (d, J = 8.8 Hz, 1H), 11.51 (brs, 1H); MS (ESI ) (M + H) +409.0. Example 31 N- [4-Chloro-2-[[〇 (Tetrahydro-2H-piperan-4-yl) ethyl] amino] carbonyl] phenyl] -1 -Carboxamide

101539 • 60· 200539856 按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1-莕基）-4Η-3，1-苯并$畊-4-酮（100毫克，0.33毫 莫耳）及4-(胺基乙基）四氫哌喃（86毫克，0·66毫莫耳），提供 標題化合物（119 毫克，83%)。iHNMRGOOMHACDClg) δ 1.38 (m，2Η)，1.59 (m，5Η)，3·31 (m，2Η)，3·43 (m，2Η)，3.92 (m，2Η)，6.15 (m， 1H)，7·51 (m，1H)，7·57 (m，4H)，7.84 (dd，J=7.6, 1.2 Hz，1H)，7·90 (m，1H)， 7.98 (d，J=8.4 Hz，1H)，8_51 (d，J=8.8 Hz, 1H)，8.88 (d，J=8.8 Hz，1H)，11.51 (brs，1H) ; MS (ESI) (M+H)+437.0· 實例32 N-[4-氣基-2-[[(l,3-二氧伍圜-2-基甲基）甲胺基]羰基]苯基]小莕 羧醯胺101539 • 60 · 200539856 According to the method in step A of Example 14, using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1-benzo Ghen-4-one (100 mg, 0.33 mmol) and 4- (aminoethyl) tetrahydropiperan (86 mg, 0.66 mmol) provide the title compound (119 mg, 83%). iHNMRGOOMHACDClg) δ 1.38 (m, 2Η), 1.59 (m, 5Η), 3.31 (m, 2Η), 3.43 (m, 2Η), 3.92 (m, 2Η), 6.15 (m, 1H), 7 · 51 (m, 1H), 7.57 (m, 4H), 7.84 (dd, J = 7.6, 1.2 Hz, 1H), 7.90 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H ), 8_51 (d, J = 8.8 Hz, 1H), 8.88 (d, J = 8.8 Hz, 1H), 11.51 (brs, 1H); MS (ESI) (M + H) + 437.0 · Example 32 N- [ 4-amino-2-[[(l, 3-dioxo-2-ylmethyl) methylamino] carbonyl] phenyl] berberylcarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1-莕基)-4Η-3，1_苯并嘮畊-4-酮（100毫克，〇·33毫 莫耳）及Ν-甲基_1，3-二氧伍圜-2-曱胺（78毫克，0.66毫莫耳）， 提供標題化合物（68毫克，49%)。iHNMRGOOMHACDC^)^ 3.13 (s，3H)，3·57 (m，2H)，3.70 (m，4H)，4·97 (m，1H)，7·36 (m，1H)，7.56 (m，4H)，7.77 (d，J=7.2 Hz, 1H)，7·89 (d，J=7.6 Hz，1H)，7.97 (d，J=8.0 Hz， 1H)，8.43 (m，2H)，9.15 (m，1H) ; MS (ESI) (M+H)+425.0. 101539 -61 - 200539856 實例33 N-[4-氣基-2-[[2-(2-吡啶基）-1-四氫吡咯基]羰基]苯基>1-莕羧醯胺Following step A in Example 14 using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1_benzopyrene-4-one (100 mg, 0.33 mmol) and N-methyl-1,3-dioxol-2-oxamine (78 mg, 0.66 mmol) provided the title compound (68 mg, 49%) . iHNMRGOOMHACDC ^) ^ 3.13 (s, 3H), 3.57 (m, 2H), 3.70 (m, 4H), 4.97 (m, 1H), 7.36 (m, 1H), 7.56 (m, 4H ), 7.77 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.43 (m, 2H), 9.15 (m , 1H); MS (ESI) (M + H) +425.0. 101539 -61-200539856 Example 33 N- [4-Gasyl-2-[[2- (2-pyridyl) -1-tetrahydropyrrolyl ] Carbonyl] phenyl > 1-fluorenylcarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-氣基-2-(1-莕基)-4Η-3，1-苯并吟畊-4-酮（100毫克，〇·33毫 莫耳）及2-(2-四氫吡咯基）-吡啶（98毫克，0.66毫莫耳），提供 標題化合物（68 毫克，45%)。1H NMR (400 MHz，CDC13) 5 1.93 (m， 3H)，2.42 (m，1H)，3.63 (m，1H)，3·83 (s，1H)，5.24 (m，1H)，6·80 (m，1H)， 7.17 (m，1H)，7.42 (m，3H)，7.54 (m，4H)，7.67 (m，1H)，7.92 (m，2H)，8·42 (m，1H)，8·66 (m，1H)，10.12 (s，1H) ; MS (ESI) (M+H)+456.0· 實例34 N-[4-氣基-2-[[2-(l-六氫吡啶基甲基>1-六氫吡啶基]羰基]苯 基]-1-審竣醯胺Following step A in Example 14 using diisopropylethylamine (0.5 ml), 6-amino-2- (1-fluorenyl) -4fluorene-3,1-benzoingen-4-one (100 mg, 0.33 mmol) and 2- (2-tetrahydropyrrolyl) -pyridine (98 mg, 0.66 mmol) provided the title compound (68 mg, 45%). 1H NMR (400 MHz, CDC13) 5 1.93 (m, 3H), 2.42 (m, 1H), 3.63 (m, 1H), 3.83 (s, 1H), 5.24 (m, 1H), 6.80 ( m, 1H), 7.17 (m, 1H), 7.42 (m, 3H), 7.54 (m, 4H), 7.67 (m, 1H), 7.92 (m, 2H), 8.42 (m, 1H), 8 66 (m, 1H), 10.12 (s, 1H); MS (ESI) (M + H) +456.0. Example 34 N- [4-Gas-2-[[2- (l-hexahydropyridyl) Methyl > 1-hexahydropyridyl] carbonyl] phenyl] -1-carboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺φ·5毫 升）、6_氣基·2-(1_莕基)-4Η-3，1_苯并嘮畊-4·酮（100毫克，0.33毫 101539 -62- 200539856 莫耳）及1-(2-六氫吡啶基甲基）-六氫吡啶（120毫克，0.66毫莫 耳），提供標題化合物（70毫克，43%)。iHNMRGOOMHz，CDC13) 5 1.0-5.0 (m，21H)，7·38 (brs，1H)，7·46 (m，1H)，7.54 (m，4H)，7.78 (d，J= 6.8 Hz，1H)，7.89 (m，1H)，7.97 (d，J=8.4 Hz，1H)，8.48 (m，2H); MS (ESI) (M+H)+490.0. 實例35 N-[2-[[(環己基甲基）胺基]幾基]冬甲基苯基]小茶羧醯胺According to the method of Step A in Example 14, diisopropylethylamine φ · 5 ml), 6-amino group · 2- (1_fluorenyl) -4Η-3,1_benzopyrene-4 · Ketones (100 mg, 0.33 mmol 101539 -62- 200539856 mole) and 1- (2-hexahydropyridylmethyl) -hexahydropyridine (120 mg, 0.66 mmol) provide the title compound (70 mg, 43 %). iHNMRGOOMHz, CDC13) 5 1.0-5.0 (m, 21H), 7.38 (brs, 1H), 7.46 (m, 1H), 7.54 (m, 4H), 7.78 (d, J = 6.8 Hz, 1H) , 7.89 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.48 (m, 2H); MS (ESI) (M + H) +490.0. Example 35 N- [2-[[( Hexylmethyl) amino] Jinoyl] Hydroxymethylphenyl] Tetracarboxamidine

步驟Α· N-[2_[[(環己基甲基)胺基]幾基]-4-甲基苯基]小莕羧醯胺Step A · N- [2 _ [[(Cyclohexylmethyl) amino] Jinyl] -4-methylphenyl] carboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6_甲基-2-(1-莕基）-4Η-3，1-苯并嘮畊-4-酮（80毫克，0.28毫 莫耳）及環己基曱胺（150毫克，1.3毫莫耳），提供標題化合 物（105 毫克，94%)。iHNMRGOOMHz'DCld 6 1.00(m，2H)，1.19 (m，3H)，1·56 (m，1H)，1·75 (m，5H)，2·40 (s，3H)，3·23 (m，2H)，6.24 (m，1H)， 7.38 (s，1H)，7.40 (m，1H)，7.54 (m，3H)，7.85 (m，1H)，7·89 (m，1H)，7.95 (d， J=8.4 Hz, 1H)5 8.54 (m, 1H), 8.75 (d? J=8.4 Hz, 1H)? 11.50 (brs, 1H)； 101539 -63- 200539856 MS (ESI) (M+H)+401.0. 步驟B. 6-甲基-2_(1-莕基）-4H-3，l-苯并嘮畊-4-酮Following step A in Example 14, using diisopropylethylamine (0.5 ml), 6-methyl-2- (1-fluorenyl) -4fluorene-3,1-benzopyrene-4-one (80 mg, 0.28 mmol) and cyclohexylamidate (150 mg, 1.3 mmol) provided the title compound (105 mg, 94%). iHNMRGOOMHz'DCld 6 1.00 (m, 2H), 1.19 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 2.40 (s, 3H), 3.23 (m , 2H), 6.24 (m, 1H), 7.38 (s, 1H), 7.40 (m, 1H), 7.54 (m, 3H), 7.85 (m, 1H), 7.89 (m, 1H), 7.95 ( d, J = 8.4 Hz, 1H) 5 8.54 (m, 1H), 8.75 (d? J = 8.4 Hz, 1H)? 11.50 (brs, 1H); 101539 -63- 200539856 MS (ESI) (M + H) +401.0. Step B. 6-methyl-2_ (1-fluorenyl) -4H-3, l-benzopyrene-4-one

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基5-甲基苯甲酸（760毫克，5.0毫莫耳）、μ莕羰基 氣（1.05克，5.5毫莫耳）及HATU(2.1克，5.5毫莫耳），提供標 題化合物（1.40 克，98%)。MS(ESI)(M+H)+288.1. 實例36 N-[2-[[(環丁基甲基）胺基]羰基]-4-甲基苯基]小莕羧醯胺According to the method in step B of Example 14, diisopropylethylamine (1 ml), 2-amino 5-methylbenzoic acid (760 mg, 5.0 mmol), and μ 荇 carbonyl gas (1.05 g, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.40 g, 98%). MS (ESI) (M + H) +288.1. Example 36 N- [2-[[(Cyclobutylmethyl) amino] carbonyl] -4-methylphenyl] carboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、6-甲基-2-(1-莕基）·4Η-3，1-苯并噚畊斗酮（80毫克，0·28毫 莫耳）及環丁基甲胺（85毫克，1.0毫莫耳），提供標題化合物 (68 毫克，65%)。1HNMR(400MHz，CDC13) 5 1.74(m，2H)，1.92(m， 2H)，2·08 (m，2H)，2.55 (m，1H)，2.38 (s，3H)，3·40 (m，2H)，6.17 (m，1H)， 7·26 (s，1H)，7·38 (d，J=8.8 Hz，1H)，7.54 (m，3H)，7.88 (m，2H)，7.95 (d，J= 8.0 Hz，1H)，8.54 (d，J=7.6 Hz，1H)，8.75 (d，J=8.4 Hz，1H)，11 _51 (brs，1H); MS (ESI) (M+H)+373.0. 101539 -64- 200539856 實例37 N_[2-[[(環己基甲基）胺基]幾基]-4-氟苯基]-1·荅竣醯胺According to the method of Step A in Example 14, diisopropylethylamine (0.5 ml), 6-methyl-2- (1-fluorenyl) · 4Η-3,1-benzopyrene, ketone ketone (80 Mg, 0.28 mmol) and cyclobutylmethylamine (85 mg, 1.0 mmol) to provide the title compound (68 mg, 65%). 1HNMR (400MHz, CDC13) 5 1.74 (m, 2H), 1.92 (m, 2H), 2.08 (m, 2H), 2.55 (m, 1H), 2.38 (s, 3H), 3.40 (m, 2H), 6.17 (m, 1H), 7.26 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.54 (m, 3H), 7.88 (m, 2H), 7.95 (d , J = 8.0 Hz, 1H), 8.54 (d, J = 7.6 Hz, 1H), 8.75 (d, J = 8.4 Hz, 1H), 11 _51 (brs, 1H); MS (ESI) (M + H) +373.0. 101539 -64- 200539856 Example 37 N_ [2-[[(Cyclohexylmethyl) amino] amino] -4-fluorophenyl] -1

步驟Α· Ν-[2-[[(環己基甲基）胺基]幾基]_4_氟苯基]-1-萘羧醯胺Step A · Ν- [2-[[(Cyclohexylmethyl) amino] amino] _4_fluorophenyl] -1-naphthylcarboxamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、6-氟基-2-(1-莕基）-4Η-3，1·苯并呤畊-4-酮（80毫克，0.28毫 莫耳）及環己基甲胺（150毫克，L3毫莫耳），提供標題化合 物（106 毫克，93%)。iHNMRGOOMHACDC^) 5 1.00(m，2H)，1.19 (m，3H)，1.56 (m，1H)，1.75 (m，5H)，3.23 (m，2H)，6.21 (m，1H)，7.20 (m， 1H)，7_29 (m，1H)，7·53 (m，3H), 7·83 (m，1H)，7.88 (m，1H)，7.97 (d，J=8.0 Hz, 1H)，8.52 (m，1H)，8.87 (dd，J=9.2, 5·2 Hz，1H)，11.40 (brs，1H); MS (ESI) (M+H)+405.0. 步驟B· 6-氟基-2-(l·莕基）-4Η·3，1-苯并嘮畊冬酮Following the procedure of step A in Example 14, using diisopropylethylamine (0.5 ml), 6-fluoro-2- (1-fluorenyl) -4fluorene-3,1, benzobenzone-4-one (80 mg, 0.28 mmol) and cyclohexylmethylamine (150 mg, L3 mmol) provided the title compound (106 mg, 93%). iHNMRGOOMHACDC ^) 5 1.00 (m, 2H), 1.19 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 3.23 (m, 2H), 6.21 (m, 1H), 7.20 (m, 1H), 7_29 (m, 1H), 7.53 (m, 3H), 7.83 (m, 1H), 7.88 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.52 (m , 1H), 8.87 (dd, J = 9.2, 5.2 Hz, 1H), 11.40 (brs, 1H); MS (ESI) (M + H) +405.0. Step B · 6-Fluoro-2- ( l · fluorenyl) -4Η · 3,1-benzopyrene

101539 -65- 200539856 按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基5-氟苯甲酸（778毫克，5.0毫莫耳）、1_萘羰基氣 (1.05克，5.5毫莫耳）及HATU(2.1克，5·5毫莫耳），提供標題 化合物（1.44 克，99%)。MS (ESI) (Μ+Η)+292.1 · 實例38 Ν-[2-[[(環丁基甲基）胺基]羰基]-4-氟苯基]-1-莕羧醯胺101539 -65- 200539856 According to the method in step B of Example 14, using diisopropylethylamine (1 ml), 2-amino 5-fluorobenzoic acid (778 mg, 5.0 mmol), 1-naphthalenecarbonyl Gas (1.05 g, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.44 g, 99%). MS (ESI) (Μ + Η) +292.1 · Example 38 N- [2-[[(Cyclobutylmethyl) amino] carbonyl] -4-fluorophenyl] -1-fluorenecarboxamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、6-氟基_2-(1_茶基)-4Η-3，1_苯弁亏〃井-4-嗣（60毫克，0.206毫 莫耳）及環丁基曱胺（85毫克，L0毫莫耳），提供標題化合物 (77 毫克，99%)。iHNMRGOOMHACDC^) 5 1.72(m，2H)，1.90(m， 2H)，2.08 (m，2H)，2.54 (m，1H)，3.40 (m，2H)，6·16 (s，1H)，7.18 (dd，J=8.8, 2.8 Hz，1H)，7.29 (m，1H)，7.55 (m，3H)，7.84 (dd，J=7.2, 0·8 Hz，1H)，7.89 (dd，J=7.6，1.6 Hz，1H)，7.97 (d，J=8.0 Hz，1H)，8.51 (d，J=8.4 Hz，1H)，8.81 (dd，J=9.2，1.2 Hz，1H)，11.41 (brs，1H) ; MS (ESI) (Μ+Η)+377·0· 實例39 N-[2-[[(環己基甲基）胺基]羰基]-6-甲氧苯基]小莕羧醯胺 101539 -66- 200539856Following the method of step A in Example 14, using diisopropylethylamine (0.5 ml), 6-fluoro-2-_2- (1_theyl) -4Η-3,1_benzene 弁 depletion well-4- Rhenium (60 mg, 0.206 mmol) and cyclobutylamidamine (85 mg, L0 mmol) provided the title compound (77 mg, 99%). iHNMRGOOMHACDC ^) 5 1.72 (m, 2H), 1.90 (m, 2H), 2.08 (m, 2H), 2.54 (m, 1H), 3.40 (m, 2H), 6.16 (s, 1H), 7.18 ( dd, J = 8.8, 2.8 Hz, 1H), 7.29 (m, 1H), 7.55 (m, 3H), 7.84 (dd, J = 7.2, 0.8 Hz, 1H), 7.89 (dd, J = 7.6, 1.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.81 (dd, J = 9.2, 1.2 Hz, 1H), 11.41 (brs, 1H) ; MS (ESI) (Μ + Η) + 377 · 0 · Example 39 N- [2-[[(Cyclohexylmethyl) amino] carbonyl] -6-methoxyphenyl] berberylcarboxamide 101539- 66- 200539856

步驟Α· N-[2-[[(環己基甲基)胺基機基]冬甲氧苯基]·ι·莕羧醯胺Step A · N- [2-[[(Cyclohexylmethyl) aminomethyl] dongmethoxyphenyl] · ι · 荇 carbamidine

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、8-甲氧基·2-(1_莕基)-4Η-3，1·苯并嘮畊-4-酮（80毫克，0.264 毫莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題化 合物（92 毫克，84%)。1H NMR (400 MHz，CDC13) 5 0.98 (m，2Η)，1.16 (m，3H)，1·65 (m，4H)，1.78 (m，2H)，3·26 (m，2H)，3·92 (s，3H)，6.43 (m，1H)， 7.09 (dd，J=8.4, 1.2 Hz，1H)，7.16 (dd，J=8.0, 1.2 Hz，1H)，7.32 (d，J=8.0 Hz， 1H)，7.55 (m，3H)，7·88 (m，2H)，7.97 (d，J=8.4 Hz，1H)，8.25 (s，1H)，8.54 (dd，J=8.4, 0.8 Hz，1H) ; MS (ESI) (M+H)+417.0. 步驟B. 8-曱氧基-2-(1-莕基）-4H-3，l-苯并咩啡-4-酮Following the method of step A in Example 14, diisopropylethylamine (0.5 ml), 8-methoxy · 2- (1-fluorenyl) -4Η-3,1 · benzopyrene-4- Ketones (80 mg, 0.264 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provide the title compound (92 mg, 84%). 1H NMR (400 MHz, CDC13) 5 0.98 (m, 2Η), 1.16 (m, 3H), 1.65 (m, 4H), 1.78 (m, 2H), 3.26 (m, 2H), 3 · 92 (s, 3H), 6.43 (m, 1H), 7.09 (dd, J = 8.4, 1.2 Hz, 1H), 7.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.32 (d, J = 8.0 Hz , 1H), 7.55 (m, 3H), 7.88 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.54 (dd, J = 8.4, 0.8 Hz, 1H); MS (ESI) (M + H) +417.0. Step B. 8-Methoxy-2- (1-fluorenyl) -4H-3, l-benzofluoren-4-one

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基-3-曱氧基-苯曱酸(835毫克，5.0毫莫耳）、1_莕羰 101539 -67- 200539856 基氯（1.05克，5·5毫莫耳）及HATU(2.1克，5.5毫莫耳），提供 標題化合物（1.49 克，98%)。MS (ESI) (M+H)+304.1. 實例40 N-[2-氣基-6-[[(環己基曱基）胺基]羰基]苯基]-1-莕羧醯胺Following step B in Example 14, using diisopropylethylamine (1 ml), 2-amino-3-methoxy-phenylbenzoic acid (835 mg, 5.0 mmol), 101539 -67- 200539856 based on chlorine (1.05 g, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) to provide the title compound (1.49 g, 98%). MS (ESI) (M + H) +304.1. Example 40 N- [2-Gas-6-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -1-fluorenecarboxamide

步驟Α· N-[2-氣基-6-[[(環己基曱基)胺基機基]苯基茶羧醯胺Step A · N- [2-Gas-6-[[(cyclohexylfluorenyl) aminomethyl] phenyl teacarboxamide

按照如實例14中步驟A之方法，使用二異丙基乙胺（〇.5毫 升）、8-氣基-2-(1•莕基）-4Η-3，1-苯并吟畊-4-酮（100毫克，0.33毫 莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題化合 物(34 毫克，25%)。1H NMR (400 MHz，CDC13 ) 3 0.96 (m，2H)，1.15 (m，3H)，1.56 (m，1H)，1·66 (m，3H)，1.76 (m，2H)，3·26 (t，J=6.4 Hz，2H)， 6.34 (brs31H)? 7.31 (t5 J=8.0 Hz, 1H)5 7.46 (dd? J=8.0, 1.6 Hz, 1H), 7.58 (m, 4H)，7.91 (d5 J=7.6 Hz，1H)，8.00 (d，J=8.4 Hz，1H)，8.53 (d，J=8.0 Hz，1H)， 8.59 (s, 1H) ； MS (ESI) (M+H)+421.0. 步驟B· 8-氣基-2·(1-莕基）-4H-3，l-苯并噚畊·4-酮 101539 -68 - 200539856Following step A in Example 14, using diisopropylethylamine (0.5 ml), 8-amino-2- (1 • fluorenyl) -4fluorene-3,1-benzopyrene-4 -Ketone (100 mg, 0.33 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) to provide the title compound (34 mg, 25%). 1H NMR (400 MHz, CDC13) 3 0.96 (m, 2H), 1.15 (m, 3H), 1.56 (m, 1H), 1.66 (m, 3H), 1.76 (m, 2H), 3.26 ( t, J = 6.4 Hz, 2H), 6.34 (brs31H)? 7.31 (t5 J = 8.0 Hz, 1H) 5 7.46 (dd? J = 8.0, 1.6 Hz, 1H), 7.58 (m, 4H), 7.91 (d5 J = 7.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.59 (s, 1H); MS (ESI) (M + H) +421.0 Step B · 8-Gas-2 · (1-fluorenyl) -4H-3, l-benzopyrene · 4-ketone 101539 -68-200539856

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基-3-氣苯甲酸（855毫克，5.0毫莫耳）、1-莕羰基氣 (1.05克，5.5毫莫耳）及HATU(2.1克，5·5毫莫耳），提供標題 化合物（1.53 克，99%)。MS(ESI)(M+H)+308·0· 實 例 41 Ν-[2-[[(環己基甲基）胺基]羰基]-6-甲基苯基]-1_莕羧醯胺Following step B in Example 14, diisopropylethylamine (1 ml), 2-amino-3-gas benzoic acid (855 mg, 5.0 mmol), and 1-fluorenylcarbonyl gas (1.05 g) were used. , 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.53 g, 99%). MS (ESI) (M + H) + 308 · 0 · Example 41 Ν- [2-[[(cyclohexylmethyl) amino] carbonyl] -6-methylphenyl] -1_carboxamidine

步驟Α· Ν-[2-[[(環己基甲基)胺基]叛基]-6-曱基苯基]-1_審羧醯胺Step A · Ν- [2-[[(Cyclohexylmethyl) amino] amino] -6-fluorenylphenyl] -1-carboxamidine

按照如實例14中步驟Α之方法，使用二異丙基乙胺（〇·5毫 升）、8-甲基-2·(1-莕基)·4Η-3，1-苯并噚啡斗酮（100毫克，〇·35毫 莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題化合 物（105 毫克，75%)。iHNMR(400MHz，CDCl3) 5 0.96(m，2H)，1.16 (m，3H)，1.56 (m，1H)，1.65 (m，3H)，1.76 (m，2H)，3·25 (t，J=6.4 Hz，2H)， 101539 -69- 200539856 6·19 (m，1Η)，7·27 (m，1Η)，7·35 (m，1H)，7.43 (d，J=7.6 Hz，1H)，7.55 (m， 3H), 7.90 (m? 2H)5 7.98 (d5 J=8.4 Hz, 1H), 8.52 (d, J=9.2 Hz, 1H), 9.40 (s, 1H); MS (ESI) (M+H)+401.0. 步驟B. 8-甲基_2·(1·萘基）-4H-3，l-苯并吟畊斗酮Following the procedure of step A in Example 14, diisopropylethylamine (0.5 ml), 8-methyl-2 ((1-fluorenyl) · 4'-3,1-benzopyridone (100 mg, 0.35 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provided the title compound (105 mg, 75%). iHNMR (400MHz, CDCl3) 5 0.96 (m, 2H), 1.16 (m, 3H), 1.56 (m, 1H), 1.65 (m, 3H), 1.76 (m, 2H), 3.25 (t, J = 6.4 Hz, 2H), 101539 -69- 200539856 6.19 (m, 1Η), 7.27 (m, 1Η), 7.35 (m, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.55 (m, 3H), 7.90 (m? 2H) 5 7.98 (d5 J = 8.4 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 9.40 (s, 1H); MS (ESI) (M + H) +401.0. Step B. 8-methyl_2 · (1 · naphthyl) -4H-3, l-benzopyridone

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基3-甲基苯曱酸（760毫克，5.0毫莫耳）、1-莕羰基 氣（1.05克，5.5毫莫耳）及HATU(2.1克，5·5毫莫耳），提供標 題化合物（1.39 克，97%)。MS (ESI) (Μ+Η)+288.1· 實例42 Ν-[5-氣基_2-[[(環己基甲基）胺基]羰基]苯基]-1-萘羧醯胺Following step B in Example 14, using diisopropylethylamine (1 ml), 2-amino 3-methylbenzoic acid (760 mg, 5.0 mmol), 1-fluorene carbonyl gas (1.05 G, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.39 g, 97%). MS (ESI) (Μ + Η) + 288.1 · Example 42 N- [5-Gasyl_2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -1-naphthylcarboxamide

步驟A. Ν-[5-氯基·2-[[(環己基甲基)胺基]艘基]苯基Η-莕羧醯胺Step A. N- [5-Chloro. 2-[[(Cyclohexylmethyl) amino] pyridyl] phenylfluorene-fluorenecarboxamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（〇·5毫 101539 -70- 200539856 升）、7-氯基-2-(1-莕基）-4Η-3，1-苯并崎畊-4-酮（100毫克，0.33毫 莫耳）及環己基甲胺（150毫克，1·3毫莫耳），提供標題化合 物（76毫克，55%)。WNMRGOOMHACDClOJO^CmJHXia (m，3H)，1·58 (m，1H)，1·76 (m, 5H)，3·23 (m，2H)，6.22 (m，1H)，7·13 (dd，J= 8.4, 2·0 Hz，1H)，7.43 (d，J=8.4 Hz，1H)，7·56 (m，3H)，7.85 (m，1H)，7.90 (m，1H)，7.98 (d，J=8.4 Hz，1H)，8.53 (dd，J=8.4, 1·28 Hz，1H)，9.02 (d，J=2.0 Hz，1H)，11.81 (brs，1H) ; MS (ESI) (M+H)+421.0. 步驟B· 7-氯基-2-(1-莕基）-4H-3，l-苯并噚畊-4_酮According to the method of step A in Example 14, diisopropylethylamine (0.5 mmol 101539 -70- 200539856 liter), 7-chloro-2- (1-fluorenyl) -4fluorene-3,1- Benzozaki-4-one (100 mg, 0.33 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provided the title compound (76 mg, 55%). WNMRGOOMHACDClOJO ^ CmJHXia (m, 3H), 1.58 (m, 1H), 1.76 (m, 5H), 3.23 (m, 2H), 6.22 (m, 1H), 7.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.56 (m, 3H), 7.85 (m, 1H), 7.90 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.53 (dd, J = 8.4, 1.28 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 11.81 (brs, 1H); MS (ESI) (M + H) +421.0. Step B 7-Chloro-2- (1-fluorenyl) -4H-3, l-benzopyrene-4_one

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基-4-氣苯甲酸（855毫克，5.0毫莫耳）、1-莕羰基氣 (1.05克，5.5毫莫耳）及與HATU(2.1克，5·5毫莫耳），提供標 題化合物（1.45 克，94%)。MS (ESI) (Μ+Η)+308.0· 實例43 Ν-[3-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-1-莕羧醯胺Following step B in Example 14, diisopropylethylamine (1 ml), 2-amino-4-gas benzoic acid (855 mg, 5.0 mmol), and 1-fluorenylcarbonyl gas (1.05 g) were used. , 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.45 g, 94%). MS (ESI) (Μ + Η) + 308.0 · Example 43 N- [3-Gasyl-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -1-fluorenecarboxamide

步驟Α· Ν_[3·氣基·2-[[(環己基曱基)胺基]毅基]苯基]小蒸羧醯胺 101539 -71 - 200539856Step A · Ν_ [3 · Amino group · 2-[[(Cyclohexylfluorenyl) amine] Amino] phenyl] phenyl] petrolamine 101539 -71-200539856

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、5-氣基-2-(1-荅基）-4Η-3，1-苯并崎畊-4·酮（100毫克，0.33毫 莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題化合 物（128 毫克，92%)。iHNMRGOOMHiCDCb) 5 0.98(m，2H)，1.18 (m，3H)，1.58 (m，1H)，1.64 (m，3H)，1_74 (m，2H)，3.28 (m，2H)，6·25 (m， 1H)，7.23 (dd，J=8.0, 〇·8 Hz，1H)，7·43 (m，1H)，7·54 (m，3H)，7.77 (dd，J= 6.8, 1.2 Hz, 1H), 7.89 (m, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.48 (m, 2H), 9.73 (brs，1H) ; MS (ESI) (M+H)+421.0. 步驟B. 5-氣基-2_(1-莕基）-4H-3，l-苯并哼啡-4_酮Following the procedure as in step A in Example 14, using diisopropylethylamine (0.5 ml), 5-amino-2- (1-fluorenyl) -4fluorene-3,1-benzozaki-4.one (100 mg, 0.33 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provided the title compound (128 mg, 92%). iHNMRGOOMHiCDCb) 5 0.98 (m, 2H), 1.18 (m, 3H), 1.58 (m, 1H), 1.64 (m, 3H), 1_74 (m, 2H), 3.28 (m, 2H), 6.25 (m , 1H), 7.23 (dd, J = 8.0, 0.8 Hz, 1H), 7.43 (m, 1H), 7.54 (m, 3H), 7.77 (dd, J = 6.8, 1.2 Hz, 1H ), 7.89 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.48 (m, 2H), 9.73 (brs, 1H); MS (ESI) (M + H) +421.0. Step B. 5-Amino-2_ (1-fluorenyl) -4H-3, l-benzohumorin-4_one

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2_胺基_6_氣苯甲酸（855毫克，5.0毫莫耳）、1-莕羰基氣 (1.05克，5.5毫莫耳）及HATU(2.1克，5.5毫莫耳），提供標題 化合物（1.50 克，98%)。MS(ESI)(M+H)+308.0· 實例44 N-[3-氣基-2-[[(環丁基甲基）胺基]羰基]苯基]-1-茶叛醯胺 101539 -72- 200539856Following step B in Example 14, diisopropylethylamine (1 ml), 2-amino-6-benzoic acid (855 mg, 5.0 mmol), and 1-fluorenylcarbonyl gas (1.05 g) were used. , 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.50 g, 98%). MS (ESI) (M + H) + 308.0 · Example 44 N- [3-Gas-2--2-[[(cyclobutylmethyl) amino] carbonyl] phenyl] -1-Tetramethylamine 101539 -72- 200539856

按照如實例14中步驟A之方法，使用5-氣基-2-(1-茶 基）-4Η-3，1_苯并呤啡斗酮（716毫克，2·33毫莫耳）與環丁基甲 胺（5·3Μ，在MeOH中，0.88毫升，4·66毫莫耳），提供標題化 合物（849 毫克，93%)。iHNMRGOOMHACDC^) 5 1.73(m，2H) 1.86 (m, 2H) 2.05 (m, 2H) 2.56 (m, 1H) 3.45 (dd, J=7.23,5.86 Hz, 2H) 6.20 (m, 1H) 7.22 (dd, J=8.01, 0.98 Hz, 1H) 7.43 (t, J=8.30 Hz, 1H) 7.55 (m, 3H) 7.78 (dd, J=7.03,1.17 Hz, 1H) 7.90 (m, 1H) 7.98 (d, J=8.40 Hz, 1H) 8.48 (m, 2H) 9.75 (s，1H) ; MS (ESI) (M+H)+ 393.0 ;對 C2 3 H2 丨 C1N2 02 之分析 計算值：C，70.31 ; H，5.39 ; N，7·13·實測值：C，70.54 ; H，5·62 ; N, 7.05. 實例45 • Ν-[2·[[(環己基甲基）胺基]幾基]-3-甲基苯基]-1_莕羧醢胺Following the procedure as in step A in Example 14, 5-amino-2- (1-theyl) -4Η-3,1_benzoxorphinone (716 mg, 2.33 mmol) was used with Butylmethylamine (5.3 M in MeOH, 0.88 ml, 4.66 mmol) provided the title compound (849 mg, 93%). iHNMRGOOMHACDC ^) 5 1.73 (m, 2H) 1.86 (m, 2H) 2.05 (m, 2H) 2.56 (m, 1H) 3.45 (dd, J = 7.23, 5.86 Hz, 2H) 6.20 (m, 1H) 7.22 (dd , J = 8.01, 0.98 Hz, 1H) 7.43 (t, J = 8.30 Hz, 1H) 7.55 (m, 3H) 7.78 (dd, J = 7.03, 1.17 Hz, 1H) 7.90 (m, 1H) 7.98 (d, J = 8.40 Hz, 1H) 8.48 (m, 2H) 9.75 (s, 1H); MS (ESI) (M + H) + 393.0; Analytical calculation for C2 3 H2 丨 C1N2 02: C, 70.31; H, 5.39; N, 7.13. Found: C, 70.54; H, 5.62; N, 7.05. Example 45 • Ν- [2 · [[(cyclohexylmethyl) amino] amido] -3- Methylphenyl] -1_carboxamidine

步驟Α· N-[2-[[(環己基甲基）胺基]羰基]-3-甲基苯基]-1-莕羧醯胺 101539 -73- 200539856Step A · N- [2-[[(Cyclohexylmethyl) amino] carbonyl] -3-methylphenyl] -1-fluorenecarboxamide 101539 -73- 200539856

按照如實例14中步驟A之方法，使用二異丙基乙胺（0.5毫 升）、5-甲基-2-(1-莕基)-4Η-3，1-苯并噚畊-4-酮（100毫克，0.35毫 莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題化合 物（102 毫克，73%)。1HNMR(400MHz，CDC13) 5 0.91 (m，2H)，1.07 (m，3H)，1·54 (m，1H)，1.59 (m，3H)，1.68 (m，2H)，2.43 (s，3H)，3·25 (t, J= 6.4 Hz5 2H)5 5.97 (brs, 1H)5 7.06 (d, J=7.6 Hz, 1H), 7.38 (t5 J=8.0 Hz, 1H), 7.53 (m，3H)，7.74 (dd，J=7.2，l ·2 Hz，1H)，7.88 (m，1H)，7.97 (d，J=7.6 Hz， lH)，8.17(d，J=8.4Hz，lH)，8.45(m，lH)，8.93(s，lH) ; MS(ESI)(M+H)+ 401.0. 步驟B· 5-甲基-2-(1-莕基）-4H-3，l-苯并嘮畊-4-酮Following step A in Example 14 using diisopropylethylamine (0.5 ml), 5-methyl-2- (1-fluorenyl) -4fluorene-3,1-benzopyrene-4-one (100 mg, 0.35 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provided the title compound (102 mg, 73%). 1HNMR (400MHz, CDC13) 5 0.91 (m, 2H), 1.07 (m, 3H), 1.54 (m, 1H), 1.59 (m, 3H), 1.68 (m, 2H), 2.43 (s, 3H) , 3.25 (t, J = 6.4 Hz5 2H) 5 5.97 (brs, 1H) 5 7.06 (d, J = 7.6 Hz, 1H), 7.38 (t5 J = 8.0 Hz, 1H), 7.53 (m, 3H) , 7.74 (dd, J = 7.2, 1.2 Hz, 1H), 7.88 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 8.45 ( m, lH), 8.93 (s, lH); MS (ESI) (M + H) + 401.0. Step B · 5-methyl-2- (1-fluorenyl) -4H-3, l-benzofluorene Phen-4-one

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基6-曱基苯甲酸（760毫克，5.0毫莫耳）、1-莕羰基 氣（1·05克，5.5毫莫耳）及HATU(2.1克，5.5毫莫耳），提供標 題化合物（1.30 克，91%)。MS(ESI)(M+H)+288_1· 實例46 N-[2-[[(環己基甲基）胺基]Μ基]·4,5-二曱氧基苯基]-1_茶羧醯胺 101539 -74- 200539856Following step B in Example 14, diisopropylethylamine (1 ml), 2-amino 6-fluorenylbenzoic acid (760 mg, 5.0 mmol), and 1-fluorenylcarbonyl gas (1 · 05 grams, 5.5 millimoles) and HATU (2.1 grams, 5.5 millimoles) provided the title compound (1.30 grams, 91%). MS (ESI) (M + H) + 288_1 · Example 46 N- [2-[[(Cyclohexylmethyl) amino] M group] · 4,5-dimethoxyphenyl] -1_teacarboxyl Lamine 101539 -74- 200539856

步驟A_ N-[2-[[(環己基曱基）胺基機基]-4,5-二甲氧基苯基]小莕 羧醯胺Step A_N- [2-[[(Cyclohexylfluorenyl) aminoamino] -4,5-dimethoxyphenyl] bemaridine Carboxamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、6,7-二甲氧基·2·(1_莕基)-4Η-3，1·苯并噚啩_4_酮（100毫克， 0·30毫莫耳）及環己基甲胺（150毫克，1.3毫莫耳），提供標題 化合物（119 毫克，89%)。1H NMR (400 MHz，CDC13) 5 0.98 (m，2Η)， 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.23 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 4.05 (s, 3H), 6.09 (brs, 1H), 6.93 (s, 1H), 7.53 (m, 3H), 7,86 (dd, J=6.8,1.2 Hz，1H)，7.89 (dd5 J=7.6, 2.0 Hz，1H)，7.96 (d，J=8.0 Hz，1H)，8.54 (d，J=9.2 Hz，1H)，8.68 (s，1H)，11.88 (s，1H) ; MS (ESI) (M+H)+447.0· 步驟B· 6,7_二甲氧基-2-(1-莕基）-4H-3，l-苯并呤啡斗酮Following the method of step A in Example 14, diisopropylethylamine (0.5 ml), 6,7-dimethoxy · 2 · (1-fluorenyl) -4Η-3,1 · benzopyrene 4-Ketone (100 mg, 0.30 mmol) and cyclohexylmethylamine (150 mg, 1.3 mmol) provided the title compound (119 mg, 89%). 1H NMR (400 MHz, CDC13) 5 0.98 (m, 2Η), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.23 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 4.05 (s, 3H), 6.09 (brs, 1H), 6.93 (s, 1H), 7.53 (m, 3H), 7,86 (dd, J = 6.8, 1.2 Hz, 1H), 7.89 (dd5 J = 7.6, 2.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 9.2 Hz, 1H), 8.68 (s, 1H), 11.88 (s, 1H) ; MS (ESI) (M + H) + 447.0 · Step B · 6,7_dimethoxy-2- (1-fluorenyl) -4H-3, l-benzoxorphinone

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 101539 -75- 200539856 升）、2-胺基4,5-二甲氧基-苯甲酸（990毫克，5·0毫莫耳）、μ 莕羰基氯（1·〇5克，5.5毫莫耳）及HATU (2.1克，5.5毫莫耳）， 提供標題化合物（1·28 克，77%)。MS(ESI)(M+H)+334.1. 實例47 Ν·[2-[[(環己基甲基）胺基]幾基]_3_甲氧苯基]小蕃緩醯胺Following the procedure as in step B in Example 14, diisopropylethylamine (1 mmol 101539 -75- 200539856 liters), 2-amino 4,5-dimethoxy-benzoic acid (990 mg, 5.0 Mmol), μ 、 carbonyl chloride (1.05 g, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.28 g, 77%). MS (ESI) (M + H) +334.1. Example 47 Ν · [2-[[(Cyclohexylmethyl) amino] amido] _3_methoxyphenyl] benzamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（0.5毫 升）、5-甲氧基-2·(1-莕基）-4Η-3，1-苯并吟畊斗酮（303毫克，1.0 毫莫耳）及環己基甲胺（300毫克，2.6毫莫耳），提供標題化 合物（350 毫克，84%)。iHNMR(400MHz，CDC13) 5 0.99(m，2H)， 1·22 (m，3H)，1·56 (m，1H)，1·74 (m，5H)，3·23 (m，2H)，3.89 (s，3H)，6.78 (dd，J=8.4,0.8 Hz，1H)，7.52 (m，4H)，7.80 (s，1H)，7.86 (m，2H)，7.95 (d，J= 8.0 Hz，1H)，8·53 (d，J=7.6 Hz，1H)，8.58 (dd，J=8.4, 0·8 Hz，1H)，12.52 (s， 1H); MS (ESI) (M+H)+417.0. 步驟B· 5-曱氧基-2_(1_莕基）-4H-3，l-苯并嘮啩-4-酮 101539 -76- 200539856According to the method of step A in Example 14, diisopropylethylamine (0.5 ml), 5-methoxy-2 · (1-fluorenyl) -4fluorene-3,1-benzinopentone ( 303 mg, 1.0 mmole) and cyclohexylmethylamine (300 mg, 2.6 mmoles) provided the title compound (350 mg, 84%). iHNMR (400MHz, CDC13) 5 0.99 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.23 (m, 2H), 3.89 (s, 3H), 6.78 (dd, J = 8.4, 0.8 Hz, 1H), 7.52 (m, 4H), 7.80 (s, 1H), 7.86 (m, 2H), 7.95 (d, J = 8.0 Hz , 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.58 (dd, J = 8.4, 0.8 Hz, 1H), 12.52 (s, 1H); MS (ESI) (M + H) +417.0. Step B. 5-Amino-2-oxo-2- (1_fluorenyl) -4H-3, l-benzofluoren-4-one 101539 -76- 200539856

按照如實例14中步驟B之方法，使用二異丙基乙胺（1毫 升）、2-胺基-6-甲氧基-苯甲酸（840毫克，5.0毫莫耳）、μ審幾 基氣（1.05克，5.5毫莫耳）及HATU(2.1克，5·5毫莫耳），提供 標題化合物（1.33 克，88%)。MS (ESI) (Μ+Η)+304.1.Following the procedure of Step B in Example 14, diisopropylethylamine (1 ml), 2-amino-6-methoxy-benzoic acid (840 mg, 5.0 mmol) was used, and the pH was measured. (1.05 g, 5.5 mmol) and HATU (2.1 g, 5.5 mmol) provided the title compound (1.33 g, 88%). MS (ESI) (Μ + Η) +304.1.

實例48 Ν-[2_[[(環丁基甲基）胺基]幾基]-3-甲氧苯基;μ_茶羧醯胺Example 48 Ν- [2 _ [[(Cyclobutylmethyl) amino] Jinyl] -3-methoxyphenyl; μ_teacarboxamide

按照如實例14中步驟Α之方法，使用二異丙基乙胺（〇·5毫 • 升）、5-甲氧基-2-(1-莕基）-4Η-3，1-苯并嘮畊-4·酮（61毫克，0.2 毫莫耳）及環丁基甲胺（85毫克，1.0毫莫耳），提供標題化合 物（35 毫克，45%)。iHNMRGOOMHACDCDS 1.74(m，2H)，1.92 (m，2H)，2.08 (m，2H)，2.55 (m，1H)，3.23 (m，2H)，3.89 (s，3H)，6·78 (dd，J= 8.4, 0.8 Hz，1H)，7·52 (m，4H)，7.80 (s，1H)，7.86 (m，2H)，7.95 (d，J=8.0 Hz， 1H)，8.53 (d，J=7.6 Hz，1H)，8.58 (dd，J=8.4,0.8 Hz，1H)，12.52 (s，1H); MS (ESI) (M+H)+389.0. 101539 -77- 200539856 實例49 N-[2-[[(環己基甲基）胺基]幾基]-3-經苯基]-1-莕緩醯胺Following the procedure of Step A in Example 14, diisopropylethylamine (0.5 milliliter • liter), 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1-benzofluorene were used. Geng-4 · ketone (61 mg, 0.2 mmol) and cyclobutylmethylamine (85 mg, 1.0 mmol) provide the title compound (35 mg, 45%). iHNMRGOOMHACDCDS 1.74 (m, 2H), 1.92 (m, 2H), 2.08 (m, 2H), 2.55 (m, 1H), 3.23 (m, 2H), 3.89 (s, 3H), 6.78 (dd, J = 8.4, 0.8 Hz, 1H), 7.52 (m, 4H), 7.80 (s, 1H), 7.86 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.58 (dd, J = 8.4, 0.8 Hz, 1H), 12.52 (s, 1H); MS (ESI) (M + H) +389.0. 101539 -77- 200539856 Example 49 N- [2 -[[(Cyclohexylmethyl) amino] amino] -3-ylphenyl] -1-sulfanilamide

於0°C下，將BBr3 (1毫升）添加至N-[2-[[(環己基甲基）胺基] 羰基]-3·甲氧苯基]-1-莕羧醯胺（300.0毫克，0.72毫莫耳）之 CH2C12(15毫升）溶液内。將反應混合物於室溫下攪拌過夜， 然後在真空中濃縮。使粗產物溶於EtOAc中，且以1ΜΝΗ4ΟΗ 水溶液、鹽水洗滌，並以無水MgS04脫水乾燥。於移除溶劑 後，使殘留物藉由逆相HPLC，使用20-80% CH3 CN/H2 0純化， 然後凍乾，以提供標題化合物（59毫克，20%)。1HNMR (400 MHz, CDC13) δ 〇·89 (m，2Η)，1.12 (m，3Η)，1·44 (m，1Η)，1·64 (m， 5H), 3.17 (m, 2H), 6.66 (brs, 1H), 7.28 (m, 1H), 7.54 (m, 3H), 7.83 (d, J= 7.2 Hz, 2H), 7.88 (m, 1H), 7.96 (d, J=8.0 Hz, 2H), 8.26 (m, 1H), 8.48 (d, J= 8.8 Hz，1H)，12.08 (s，1H) ; MS (ESI) (M+H)+403.0· 實例50 N-[2-[[(環丁基甲基）胺基]幾基]-3·經苯基]·1_莕羧醯胺BBr3 (1 ml) was added to N- [2-[[(cyclohexylmethyl) amino] carbonyl] -3 · methoxyphenyl] -1-carboxamidine (300.0 mg at 0 ° C) , 0.72 mmol) in a solution of CH2C12 (15 ml). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude product was dissolved in EtOAc, and washed with a 1N 40Η aqueous solution, brine, and dried over anhydrous MgS04. After removing the solvent, the residue was purified by reverse-phase HPLC using 20-80% CH3CN / H2O and then lyophilized to provide the title compound (59 mg, 20%). 1HNMR (400 MHz, CDC13) δ 0.98 (m, 2Η), 1.12 (m, 3Η), 1.44 (m, 1Η), 1.64 (m, 5H), 3.17 (m, 2H), 6.66 (brs, 1H), 7.28 (m, 1H), 7.54 (m, 3H), 7.83 (d, J = 7.2 Hz, 2H), 7.88 (m, 1H), 7.96 (d, J = 8.0 Hz, 2H) , 8.26 (m, 1H), 8.48 (d, J = 8.8 Hz, 1H), 12.08 (s, 1H); MS (ESI) (M + H) + 403.0 · Example 50 N- [2-[[( Butylmethyl) amino] Jinyl] -3 · Phenyl] · 1-carboxamidine

101539 78- 200539856 按照如實例49之方法，使用N-[2-[[(環丁基甲基）胺基]羰 基]-3-甲氧苯基]小莕羧醯胺（100.0毫克，0.26毫莫耳）與BBr3(l 毫升），提供標題化合物（22毫克，23%)。4匪11(400 MHz， CDC13) 3 1.62 (m，2H)，1·81 (m，2H)，1.98 (m，2H)，2.44 (m，1H)，3.32 (m， 2H)，6.67 (d, J=8.0 Hz，1H)，7·21 (m，1H)，7·50 (m，3H)，7.81 (d，J=6.8 Hz， 1H)，7.87 (m，1H)，7·95 (d，J=8.0 Hz，1H)，8.06 (s，1H)，8.26 (m，1H)，8.40 (d，J=8.0 Hz, 1H)，12.38 (s，1H) ; MS (ESI) (M+H)+375.2. 實例51 N-[4-氯基-2-[[(環己基曱基）胺基]羰基]苯基]-8-喳啉羧醯胺101539 78-200539856 According to the method of Example 49, using N- [2-[[(cyclobutylmethyl) amino] carbonyl] -3-methoxyphenyl] berberylcarboxamide (100.0 mg, 0.26 mmol) ) With BBr3 (1 ml) to provide the title compound (22 mg, 23%). Bandit 11 (400 MHz, CDC13) 3 1.62 (m, 2H), 1.81 (m, 2H), 1.98 (m, 2H), 2.44 (m, 1H), 3.32 (m, 2H), 6.67 (d , J = 8.0 Hz, 1H), 7.21 (m, 1H), 7.50 (m, 3H), 7.81 (d, J = 6.8 Hz, 1H), 7.87 (m, 1H), 7.95 ( d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 8.26 (m, 1H), 8.40 (d, J = 8.0 Hz, 1H), 12.38 (s, 1H); MS (ESI) (M + H) +375.2. Example 51 N- [4-Chloro-2-[[(Cyclohexylamido) amino] carbonyl] phenyl] -8-pyridinocarboxamidine

步驟A. N-[4-氯基-2-[[(環己基曱基）胺基]毅基]苯基]_8·喳啉羧 醯胺Step A. N- [4-Chloro-2-[[(cyclohexylamido) amino] amino] phenyl] phenyl] -8.

C'Y^H nh2 於0°C下，將二異丙基乙胺（127毫克，1·〇毫莫耳）添加至 2-胺基-5-氣(環己基甲基)·苯甲醯胺（134毫克，0·5毫莫耳， 關於其製備可參閱步驟Β)與8-喹啉羧酸（130毫克，0.75毫莫 耳）在DMF (10毫升）中之溶液内。於攪拌20分鐘後，添加 101539 -79- 200539856 HATU (570毫克，1.5毫莫耳）。將反應混合物在室溫下攪拌24 小時，然後以H20 (50毫升）使反應淬滅。收集沉澱物，並在 真空中乾燥，以提供標題化合物（88毫克，42%)。iHNMR (400 MHz, CDC13) δ 0.95 (m，2Η)，1·01 (m，3Η)，1.45 (m，1Η)，1·56 (m， 3H)，1.64 (m，2H)，3.25 (d，J=6.4 Hz，2H)，6.19 (brs，1H)，7.45 (m，2H)，7·56 (m，1H)，7.72 (d，J=7.6 Hz，1H)，8.03 (d，J=8.4 Hz，1H)，8·31 (d，J=8.4 Hz， 1H)，8.41 (d，J=8.8 Hz，1H)，8.87 (d，J=7.6 Hz，1H)，9·11 (d，J=4_4 Hz，1H)， 13.98 (brs, 1H) ； MS (ESI) (M+H)+421.9. 步驟B· 2-胺基-5-氣-N-(環己基甲基）-苯甲酿胺C'Y ^ H nh2 Diisopropylethylamine (127 mg, 1.0 mmol) was added to 2-amino-5-gas (cyclohexylmethyl) · benzidine at 0 ° C. For amine (134 mg, 0.5 mmol, see step B) and its solution in 8-quinolinecarboxylic acid (130 mg, 0.75 mmol) in DMF (10 ml). After stirring for 20 minutes, 101539 -79- 200539856 HATU (570 mg, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, and then the reaction was quenched with H20 (50 mL). The precipitate was collected and dried in vacuo to provide the title compound (88 mg, 42%). iHNMR (400 MHz, CDC13) δ 0.95 (m, 2Η), 1.01 (m, 3Η), 1.45 (m, 1Η), 1.56 (m, 3H), 1.64 (m, 2H), 3.25 (d , J = 6.4 Hz, 2H), 6.19 (brs, 1H), 7.45 (m, 2H), 7.56 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.87 (d, J = 7.6 Hz, 1H), 9.11 (d, J = 4_4 Hz, 1H), 13.98 (brs, 1H); MS (ESI) (M + H) +421.9. Step B · 2-Amino-5-gas-N- (cyclohexylmethyl) -benzyl Stuffed Amine

於室溫下，將環己基甲胺（6·8克，60毫莫耳）添加至5-氣 基伊沙東（isatonic)酸酐（6.0克，30毫莫耳）與二異丙基乙胺 (3·8克，30毫莫耳）在DMF (50毫升）中之溶液内。2小時後， 以AO (100毫升）與乙醚（50毫升）使反應混合物淬滅。收集 沉澱物，並在真空中乾燥，以提供標題化合物（7 〇克，87%)。 MS (ESI) (M+H)+267.1. 實例52 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]喳琳羧醯胺 101539 -80 - 200539856At room temperature, cyclohexylmethylamine (6.8 g, 60 mmol) was added to 5-isotonic acid anhydride (6.0 g, 30 mmol) and diisopropylethylamine (3.8 g, 30 mmol) in a solution in DMF (50 ml). After 2 hours, the reaction mixture was quenched with AO (100 mL) and ether (50 mL). The precipitate was collected and dried in vacuo to provide the title compound (70 g, 87%). MS (ESI) (M + H) +267.1. Example 52 N- [4-Gas-2--2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] pancarboxamidine 101539 -80-200539856

按照如實例51中步驟A之方法，使用二異丙基乙胺（381 毫克，3·0毫莫耳）、2-胺基-5-氯-N-(環己基曱基)-苯甲醯胺(400 毫克，1.5毫莫耳）、喹啉-2-羧酸(346毫克，2.0毫莫耳）及HATU (760毫克，2·0毫莫耳），提供標題化合物（380毫克，60%)。 1H NMR (400 MHz, CDC13 ) 5 1.02 (m, 2H), 1.17 (m, 3H), 1.61 (m, 2H), 1.68 (m，2H)，1.77 (m，2H)，3.35 (d，J=6.4 Hz, 2H)，6.13 (brs，1H)，7.47 (m， 2H), 7.62 (m, 1H), 7.78 (dt, J=8.4, 1.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.30 (m，3H)，8.80 (d，J=9.6 Hz, 1H)，12.75 (brs，1H) ; MS (ESI) (M+H)+422.1· 實例53 N-[4-乳基-2-[[(環己基甲基）胺基]幾基]苯基]奎〃号琳叛酿胺Following the procedure of Step A in Example 51 using diisopropylethylamine (381 mg, 3.0 mmol), 2-amino-5-chloro-N- (cyclohexylfluorenyl) -benzidine Amine (400 mg, 1.5 mmol), quinoline-2-carboxylic acid (346 mg, 2.0 mmol) and HATU (760 mg, 2.0 mmol) provide the title compound (380 mg, 60% ). 1H NMR (400 MHz, CDC13) 5 1.02 (m, 2H), 1.17 (m, 3H), 1.61 (m, 2H), 1.68 (m, 2H), 1.77 (m, 2H), 3.35 (d, J = 6.4 Hz, 2H), 6.13 (brs, 1H), 7.47 (m, 2H), 7.62 (m, 1H), 7.78 (dt, J = 8.4, 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 8.30 (m, 3H), 8.80 (d, J = 9.6 Hz, 1H), 12.75 (brs, 1H); MS (ESI) (M + H) + 422.1 · Example 53 N- [4-lactyl -2-[[(Cyclohexylmethyl) amino] Jinyl] phenyl] quinidine

於〇 C下，將氣化2-喳呤醯（148毫克，〇·75毫莫耳）在CH2C12 (〇·5毫升）中之溶液，添加至二異丙基乙胺（127毫克，1〇毫 莫耳）、2-胺基-5-氣(環己基曱基 >苯甲醯胺（134毫克，〇·5 名莫耳）在DMF (5毫升）中之混合物内。然後，將反應混合 物於室溫下攪拌2小時，接著WH2〇(2〇毫升）使反應淬滅。 101539 -81 - 200539856 收集沉澱物，並在真空中乾燥，以提供標題化合物（106毫 克，50%)。iHNMRGOOMHACDClJ 5 l.〇3(m，2H)，U9(m，3H)， 1·61 (m，2H)，1·69 (m，2H)，1.77 (m，2H)，3.34 (d，J=6.4 Hz, 2H)，6.16 (brs， 1H)，7.50 (m，2H)，7_87 (m，2H)，8.17 (m，1H)，8.31 (m，1H)，8.81 (d，J=9.2 Hz，1H)，9·69 (s，1H)，12·74 (brs，1H) ; MS (ESI) (M+H)+423.1· 實例54 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]小莕羧醯胺At 0 ° C, a solution of gasified 2-xanthopterin (148 mg, 0.75 mmol) in CH2C12 (0.5 ml) was added to diisopropylethylamine (127 mg, 1.0%). Millimoles), 2-amino-5-gas (cyclohexylfluorenyl) > benzamidine (134 mg, 0.5 mole) in DMF (5 ml). Then, the reaction was The mixture was stirred at room temperature for 2 hours, followed by quenching the reaction with WH20 (20 mL). 101539 -81-200539856 The precipitate was collected and dried in vacuo to provide the title compound (106 mg, 50%). IHNMRGOOMHACDClJ 5 l.〇3 (m, 2H), U9 (m, 3H), 1.61 (m, 2H), 1.69 (m, 2H), 1.77 (m, 2H), 3.34 (d, J = 6.4 Hz, 2H), 6.16 (brs, 1H), 7.50 (m, 2H), 7_87 (m, 2H), 8.17 (m, 1H), 8.31 (m, 1H), 8.81 (d, J = 9.2 Hz, 1H ), 9.69 (s, 1H), 12.74 (brs, 1H); MS (ESI) (M + H) +423.1. Example 54 N- [4-Gas-2-[[(cyclohexylmethyl ) Amino] carbonyl] phenyl] berberylcarboxamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2·胺基-5-氣-N-(環己基甲基)-苯甲醯胺（267毫克，1.0 毫莫耳）及氣化1-莕醯(296毫克，L5毫莫耳），提供標題化合 物（178 毫克，43%)。iHNMRGOOMH^CDC^) 6 0.99(m，2H)，1·22 (m，3Η)，1.56 (m，1Η)，1·75 (m，5Η)，3.23 (d，J=6.4 Ηζ，2Η)，6·21 (brs，1Η)， 7.46 (m，1H)，7.53 (m，4H)，7.84 (dd，J=7.2,1.2 Hz，1H)，7·89 (m，1H)，7.97 (d，J=8.0 Hz，1H)，8_52 (m，1H)，8.88 (d，J=9.2 Hz，1H)，11.53 (brs，1H); MS (ESI) (M+H)+420.9. 實例55 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基>3-喳啉羧醯胺 101539 -82- 200539856Following the method as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2.amino-5-gas-N- (cyclohexylmethyl) -benzamide (267 mg, 1.0 millimolar) and vaporized 1-amidine (296 mg, L5 millimolar) to provide the title compound (178 mg, 43%). iHNMRGOOMH ^ CDC ^) 6 0.99 (m, 2H), 1.22 (m, 3Η), 1.56 (m, 1Η), 1.75 (m, 5Η), 3.23 (d, J = 6.4 Ηζ, 2Η), 6.21 (brs, 1Η), 7.46 (m, 1H), 7.53 (m, 4H), 7.84 (dd, J = 7.2, 1.2 Hz, 1H), 7.89 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8_52 (m, 1H), 8.88 (d, J = 9.2 Hz, 1H), 11.53 (brs, 1H); MS (ESI) (M + H) +420.9. Example 55 N- [4-Amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl > < 3-phosphonocarboxamide 101539 -82- 200539856

按照如實例51中步驟A之方法，使用二異丙基乙胺（190 毫克，1.5毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯甲醯胺（187 毫克，〇·7毫莫耳）、3-喳啉羧酸（173毫克，1.0毫莫耳）及HATU (380毫克，1.0毫莫耳），提供標題化合物（25毫克，8.5%)。 1H NMR (400 MHz, CDC13) 5 1.00 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1·75 (m，5H)，3.30 (d，J=6.4 Hz，2H)，6·26 (brs，1H)，7·48 (m，1H)，7·51 (m， 1H)，7·62 (m，1H)，7.81 (m，1H)，7·99 (d，J=7.2 Hz，1H)，8.15 (d，J=8.0 Hz， 1H)，8·74 (s，1H)，8·80 (d，J=9.2 Hz，1H)，9.50 (s，1H)，12·38 (brs，1H); MS (ESI) (M+H)+422.1. 實例56 N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-2-吡畊羧醯胺Following step A of Example 51 using diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide ( 187 mg, 0.7 millimolar), 3-phosphonocarboxylic acid (173 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) provided the title compound (25 mg, 8.5%). 1H NMR (400 MHz, CDC13) 5 1.00 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 3.30 (d, J = 6.4 Hz, 2H) , 6.26 (brs, 1H), 7.48 (m, 1H), 7.51 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.99 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.74 (s, 1H), 8.80 (d, J = 9.2 Hz, 1H), 9.50 (s, 1H), 12 · 38 (brs, 1H); MS (ESI) (M + H) +422.1. Example 56 N- [4-Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl]- 2-pyroxycarboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（190 毫克，1.5毫莫耳）、2-胺基-5-氯-N-(環己基甲基)-苯甲醯胺（134 毫克，0.5毫莫耳）、2-吡畊羧酸（186毫克，1.5毫莫耳）及HATU (570毫克，1·5毫莫耳），提供標題化合物（1〇3毫克，55%)。 101539 -83- 200539856 1H NMR (400 MHz，CDC13) 5 1.04 (m，2H)，1.24 (m，3H)，1.57 (m，1H)， 1.74 (m，5H)，3.34 (t，J=6.4 Hz，2H)，6·22 (brs，1H)，7.49 (m，2H)，8.73 (s， 1H)，8.79 (m，2H)，9.47 (s，1H)，12.65 (brs，1H) ; MS (ESI) (Μ+Η)+373·1· 實例57 N-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-3-嗒畊羧醯胺Following step A of Example 51 using diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-chloro-N- (cyclohexylmethyl) -benzamide ( 134 mg, 0.5 millimolar), 2-picolinic acid (186 mg, 1.5 millimolar), and HATU (570 mg, 1.5 millimolar) provide the title compound (103 mg, 55%) . 101539 -83- 200539856 1H NMR (400 MHz, CDC13) 5 1.04 (m, 2H), 1.24 (m, 3H), 1.57 (m, 1H), 1.74 (m, 5H), 3.34 (t, J = 6.4 Hz , 2H), 6.22 (brs, 1H), 7.49 (m, 2H), 8.73 (s, 1H), 8.79 (m, 2H), 9.47 (s, 1H), 12.65 (brs, 1H); MS ( ESI) (Μ + Η) + 373 · 1 · Example 57 N- [4-Gamo-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -3-carboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（190 毫克，1.5毫莫耳）、2-胺基-5_氣-N-(環己基甲基)-苯曱醯胺（134 毫克，0.5毫莫耳）、3-嗒畊羧酸（186毫克，L5毫莫耳）及HATU (570毫克，1.5毫莫耳），提供標題化合物（105毫克，56%)。 1H NMR (400 MHz, CDC13) 5 1 ·02 (m，2H)，1.24 (m，3H)，1.74 (m，6H)， 3.35 (t，J=6.4 Hz，2H)，6.20 (brs，1H)，7·51 (m，2H)，7.69 (m，1H)，8.36 (d，J= 10.0 Hz，1H)，8.81 (d，J=10.0 Hz，1H)，9.34 (s，1H)，13.06 (brs，1H); MS (ESI) (M+H)+373.1. 實例58 N-[4-氣基_2-[[(環己基曱基）胺基]羰基]苯基]-2-莕羧醯胺Following the procedure as in step A in Example 51 using diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-amino-N- (cyclohexylmethyl) -phenylhydrazine ( 134 mg, 0.5 mmol., 3-Da-Chen Carboxylic Acid (186 mg, L5 mmol.) And HATU (570 mg, 1.5 mmol.) Provided the title compound (105 mg, 56%). 1H NMR (400 MHz, CDC13) 5 1 · 02 (m, 2H), 1.24 (m, 3H), 1.74 (m, 6H), 3.35 (t, J = 6.4 Hz, 2H), 6.20 (brs, 1H) , 7.51 (m, 2H), 7.69 (m, 1H), 8.36 (d, J = 10.0 Hz, 1H), 8.81 (d, J = 10.0 Hz, 1H), 9.34 (s, 1H), 13.06 ( brs, 1H); MS (ESI) (M + H) +373.1. Example 58 N- [4-Gas_2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -2-fluorenecarboxy Amidine

101539 -84- 200539856 按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯甲醯胺（134毫克，0.5 毫莫耳）及氣化2-莕醯（148毫克，0.75毫莫耳），提供標題化 合物（109 毫克，52%)。iHNMRGOOMHACDC^) 5 1.04(m，2H)， 1·23 (m，3H)，1.79 (m，6H)，3.34 (t，J=6.4 Hz，2H)，6·32 (brs，1H)，7·49 (m， 2H)，7.58 (m，2H)，8·04 (m，4H)，8.55 (s，1H)，8·84 (d，J=8.8 Hz，1H)，12.15 (brs，1H) ; MS (ESI) (M+H)+421.1· 實例59101539 -84- 200539856 According to the method of Example 53, using diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzidine Amine (134 mg, 0.5 mmol) and vaporized 2-Hg (148 mg, 0.75 mmol) provided the title compound (109 mg, 52%). iHNMRGOOMHACDC ^) 5 1.04 (m, 2H), 1.23 (m, 3H), 1.79 (m, 6H), 3.34 (t, J = 6.4 Hz, 2H), 6.32 (brs, 1H), 7 · 49 (m, 2H), 7.58 (m, 2H), 8.04 (m, 4H), 8.55 (s, 1H), 8.84 (d, J = 8.8 Hz, 1H), 12.15 (brs, 1H) ; MS (ESI) (M + H) +421.1

N-[4-氣基冬[[(環己基甲基）胺基]羰基]苯基]_4-吡啶羧醯胺N- [4-Aminoyl [[(cyclohexylmethyl) amino] carbonyl] phenyl] _4-pyridinecarboxamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯甲醯胺（134毫克，0.5 毫莫耳）及氣化異菸鹼醯鹽酸鹽（135毫克，0.75毫莫耳），提 供標題化合物（27 毫克，14%)。1H NMR (400 MHz，CDC13) 5 1.02 (m，2H)，1.24 (m，3H)，1.74 (m，6H)，3.29 (t，J=6.4 Hz，2H)，6·28 (brs，1H)， 7.45 (m，1H)，7·47 (m，1H)，7.81 (dd，J=4.4,1·6 Hz，2H)，8·79 (m，3H)，12.30 (brs，1H) ; MS (ESI) (M+H)+372.1. 實例60 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-3-吡啶羧醯胺 101539 -85 - 200539856Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide (134 mg, 0.5 mmol) and vaporized isonicotinium hydrochloride (135 mg, 0.75 mmol) to provide the title compound (27 mg, 14%). 1H NMR (400 MHz, CDC13) 5 1.02 (m, 2H), 1.24 (m, 3H), 1.74 (m, 6H), 3.29 (t, J = 6.4 Hz, 2H), 6.28 (brs, 1H) , 7.45 (m, 1H), 7.47 (m, 1H), 7.81 (dd, J = 4.4, 1.6 Hz, 2H), 8.79 (m, 3H), 12.30 (brs, 1H); MS (ESI) (M + H) +372.1. Example 60 N- [4-Gamo-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3-pyridinecarboxamide 101539 -85- 200539856

按照如實例53之方法，使用二異丙基乙胺（190毫克，1·5 毫莫耳）、2-胺基-5-氣_Ν-(環己基甲基）_苯甲醯胺（134毫克，0·5 毫莫耳）及氯化菸鹼醯鹽酸鹽（135毫克，0.75毫莫耳），提供 標題化合物（24 毫克，13%)。1H NMR (400 MHz，CDC13) 5 1.04 (m， 2H), 1.23 (m, 3H), 1.79 (m, 6H), 3.32 (t, J=6.4 Hz, 2H), 6.29 (brs, 1H), 7.48 (m，3H)，8.28 (m，1H)，8.79 (m，2H)，9.27 (s，1H)，12.25 (brs，1H); MS (ESI) (M+H)+372.1. 實例61 2-(苯甲醯胺基）_5-氣-N-(環己基甲基）-苯甲醯胺Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-amino_N- (cyclohexylmethyl) _benzamide (134 Mg, 0.5 millimolar) and nicotinic chloride hydrazone hydrochloride (135 mg, 0.75 millimolar) provided the title compound (24 mg, 13%). 1H NMR (400 MHz, CDC13) 5 1.04 (m, 2H), 1.23 (m, 3H), 1.79 (m, 6H), 3.32 (t, J = 6.4 Hz, 2H), 6.29 (brs, 1H), 7.48 (m, 3H), 8.28 (m, 1H), 8.79 (m, 2H), 9.27 (s, 1H), 12.25 (brs, 1H); MS (ESI) (M + H) +372.1. Example 61 2- (Benzamidine) _5-Ga-N- (cyclohexylmethyl) -benzamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基曱基)-苯甲醯胺（134毫克，0.5 毫莫耳）及氣化苯甲醯（105毫克，0.75毫莫耳），提供標題化 合物（75 毫克，41%)。1H NMR (400 MHz，CDC13) 5 1-04 (m，2H)，1.25 (m，3H)，1.59 (m，1H)，1.78 (m，5H)，3_32 (d，J=6.4 Hz，2H)，6·25 (brs，1H)， 7.50 (m, 5H), 8.02 (dd, J=6.85 1.2 Hz, 2H), 8.81 (d5 J=8.8 Hz, 1H), 11.96 101539 -86 - 200539856 (brs，1H) ; MS (ESI) (M+H)+371.1. 實例62 N-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-3,4-二氫-2H-1，5-苯 并二氧氮七圜烯-7_羧醯胺Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylfluorenyl) -benzamide (134 mg, 0.5 mmol) and vaporized benzamidine (105 mg, 0.75 mmol) to provide the title compound (75 mg, 41%). 1H NMR (400 MHz, CDC13) 5 1-04 (m, 2H), 1.25 (m, 3H), 1.59 (m, 1H), 1.78 (m, 5H), 3_32 (d, J = 6.4 Hz, 2H) , 6.25 (brs, 1H), 7.50 (m, 5H), 8.02 (dd, J = 6.85 1.2 Hz, 2H), 8.81 (d5 J = 8.8 Hz, 1H), 11.96 101539 -86-200539856 (brs, 1H); MS (ESI) (M + H) +371.1. Example 62 N- [4-Gas-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -3,4-dihydro -2H-1,5-benzodioxazepine-7-carboxamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基曱基）-苯甲醯胺（134毫克，0.5 毫莫耳）及3,4-二氫-2H-1，5-苯并二氧氮七圜烯-7-氣化碳醯 (160毫克，0.75毫莫耳），提供標題化合物（36毫克，16%)。 1H NMR (400 MHz, CDC13) δ 0.98 (m, 2Η), 1.17 (m, 3H), 1.59 (m, 1H), 1.73 (m，5H)，2.19 (m，2H)，3.25 (d，J=6.4 Hz，2H)，4.25 (m，4H)，6.55 (m， 1H)，7.00 (d，J=8.4 Hz，1H)，7.39 (m，1H)，7·49 (dd，J=8.4, 2·4 Hz，1H)，7.57 (d，J=2.4 Hz，1H)，8_61 (d，J=8.8 Hz，1H)，11.74 (brs，1H); MS (ESI) (M+H)+ 443.1. 實例63 N-[4-氣基-2-[[(環己基曱基)胺基]羰基]苯基]-2,3-二氫-7-苯并呋 喃羧醯胺 101539 -87- 200539856Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylfluorenyl) -benzamide (134 mg, 0.5 mmol) and 3,4-dihydro-2H-1,5-benzodiazepine heptaene-7-gasified carbohydrate (160 mg, 0.75 mmol) to provide the title compound (36 mg , 16%). 1H NMR (400 MHz, CDC13) δ 0.98 (m, 2Η), 1.17 (m, 3H), 1.59 (m, 1H), 1.73 (m, 5H), 2.19 (m, 2H), 3.25 (d, J = 6.4 Hz, 2H), 4.25 (m, 4H), 6.55 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.39 (m, 1H), 7.49 (dd, J = 8.4, 2 4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 8_61 (d, J = 8.8 Hz, 1H), 11.74 (brs, 1H); MS (ESI) (M + H) + 443.1. Example 63 N- [4-Gamo-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -2,3-dihydro-7-benzofurancarboxamide 101539 -87- 200539856

按照如實例51中步驟A之方法，使用二異丙基乙胺（127 毫克，1·〇毫莫耳）、2-胺基-5-氯-N-(環己基曱基）·苯甲醯胺（Π4 毫克，〇·5毫莫耳）、2,3-二氫苯并呋喃-7·羧酸(99毫克，0.6毫 莫耳）及HATU(380毫克，L0毫莫耳），藉由逆相HPLC純化 後，提供標題化合物（15毫克，7%)。iHNMRGOOMHACDClJ 5 0.96 (m，2H)，U7 (m，3H)，L56 (m，1H)，1.71 (m，5H)，3.22 (m，4H)， 4.78 (t，J=8.4 Hz，2H)，6.13 (brs，1H)，6.93 (t，J=7.6 Hz，1H)，7.31 (dd，J=7.2, 1·2 Hz，1H)，7·37 (m，1H)，7.84 (d，J=7.6 Hz，1H)，8.45 (d，J=9.2 Hz，1H)， 11.01 (brs，1H) ; MS (ESI) (Μ+Η)+413·1· 實例64 N-[4_氣基-2-[[(環己基曱基）胺基]羰基]苯基]-i-異喳啉羧醯胺Following step A in Example 51 using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-chloro-N- (cyclohexylfluorenyl) · benzidine Amine (Π 4 mg, 0.5 mmol), 2,3-dihydrobenzofuran-7 · carboxylic acid (99 mg, 0.6 mmol) and HATU (380 mg, L0 mmol) After purification by reverse phase HPLC, the title compound (15 mg, 7%) was provided. iHNMRGOOMHACDClJ 5 0.96 (m, 2H), U7 (m, 3H), L56 (m, 1H), 1.71 (m, 5H), 3.22 (m, 4H), 4.78 (t, J = 8.4 Hz, 2H), 6.13 (brs, 1H), 6.93 (t, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.2, 1.2 Hz, 1H), 7.37 (m, 1H), 7.84 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 9.2 Hz, 1H), 11.01 (brs, 1H); MS (ESI) (Μ + Η) + 413 · 1 · Example 64 N- [4_ 气 基 -2- [[(Cyclohexylfluorenyl) amino] carbonyl] phenyl] -i-isophospholinecarboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（127 毫克，1.0毫莫耳）、2-胺基-5-氣-N-(環己基曱基）-笨曱醯胺（134 毫克，〇·5毫莫耳）、1-異喳啉羧酸（173毫克，1·0毫莫耳）及 HATU (380毫克，ι·〇毫莫耳），藉由逆相Hplc純化後，提供 101539 -88 - 200539856 標題化合物（28 毫克，13%)。1HNMR(400MHz，CDCl3) 5 0.99 (m，2H)，1·17 (m，3H)，1.56 (m，1H)，1·72 (m，5H)，3.30 (t，J=6.4 Hz，2H)， 6.14 (brs，1H)，7.46 (m，2H)，7.67 (m，2H)，7·84 (m，2H)，8·63 (d，J=5.6 Hz， 1H)，8·81 (d，J=8.8 Hz，1H)，9.49 (d，J=9.2 Hz，1H)，12.60 (brs，1H); MS (ESI) (M+H)+422.1· 實例65 N-[4-氣基-2_[[(環己基甲基）胺基]羰基]苯基]_4-喹啉羧醯胺Following step A of Example 51 using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas-N- (cyclohexylfluorenyl) -benzylamine ( 134 mg, 0.5 mmole), 1-isoammonocarboxylic acid (173 mg, 1.0 mmole) and HATU (380 mg, ιmole. 0 mmol), purified by reverse phase Hplc , Providing 101539 -88-200539856 of the title compound (28 mg, 13%). 1HNMR (400MHz, CDCl3) 5 0.99 (m, 2H), 1.17 (m, 3H), 1.56 (m, 1H), 1.72 (m, 5H), 3.30 (t, J = 6.4 Hz, 2H) , 6.14 (brs, 1H), 7.46 (m, 2H), 7.67 (m, 2H), 7.84 (m, 2H), 8.63 (d, J = 5.6 Hz, 1H), 8.81 (d , J = 8.8 Hz, 1H), 9.49 (d, J = 9.2 Hz, 1H), 12.60 (brs, 1H); MS (ESI) (M + H) + 422.1 · Example 65 N- [4-Gas- 2 _ [[(Cyclohexylmethyl) amino] carbonyl] phenyl] _4-quinolinecarboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（127 毫克，1.0毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯甲醯胺（134 毫克，〇·5毫莫耳）、4-喳啉羧酸（173毫克，1·0毫莫耳）及HATU (380毫克，L0毫莫耳），藉由逆相HPLC純化後，提供標題化 合物（20 毫克，10%)。iHNMRGOOMHiCDsOD) 5 0.91(m，2H)， 1.17 (m5 3H), 1.68 (m5 6H)5 3.10 (d, J=6.8 Hz, 2H), 7.56 (dd5 J=8.8,2.4 Hz, 1H)，7.74 (m，1H)，7.84 (m，1H)，8.01 (m，2H)，8.18 (d，J=8.8 Hz，1H)，8.48 (m，2H)，9.16 (d，J=4.8 Hz，1H) ; MS (ESI) (M+H)+422.1· 實例66 N-[4-氣基-2-[[(環己基曱基）胺基]幾基]苯基]-4-u^琳叛醯胺 101539 •89- 200539856Following step A of Example 51 using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide ( 134 mg, 0.5 mmole), 4-phosphonocarboxylic acid (173 mg, 1.0 mmole) and HATU (380 mg, L0 mmole), after purification by reverse phase HPLC, the title is provided Compound (20 mg, 10%). iHNMRGOOMHiCDsOD) 5 0.91 (m, 2H), 1.17 (m5 3H), 1.68 (m5 6H) 5 3.10 (d, J = 6.8 Hz, 2H), 7.56 (dd5 J = 8.8, 2.4 Hz, 1H), 7.74 (m , 1H), 7.84 (m, 1H), 8.01 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 8.48 (m, 2H), 9.16 (d, J = 4.8 Hz, 1H); MS (ESI) (M + H) +422.1. Example 66 N- [4-Gas-2--2-[[(cyclohexylfluorenyl) amino] amido] phenyl] -4-u-methylamine 101539 • 89- 200539856

按照如實例51中步驟A之方法，使用二異丙基乙胺（127 毫克，1·〇毫莫耳）、2-胺基·5-氣-N-(環己基甲基）-苯甲醯胺（134 毫克，〇·5毫莫耳）、唓啉-4-羧酸（174毫克，L0毫莫耳）及HATU (380毫克，1.0毫莫耳），藉由逆相HPLC純化後，提供標題化 合物（25 毫克，12%)。iHNMRGOOMHACDsOD) 5 0.94(m，2H)， 1.17 (m，3H)，1.66 (m，6H)，3·14 (d，J=6.8 Hz，2H)，7·58 (dd，J=8.8,2·4 Hz， 1H)，7.75 (d，>2·4 Hz，1H)，7.96 (m，1H)，8·03 (m，1H)，8·51 (m，3H)，9·52 (s，1H) ; MS (ESI) (M+H)+423.1· 實例67 N-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-2-甲氧基-1-莕羧 醯胺Following step A in Example 51 using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino · 5-gas-N- (cyclohexylmethyl) -benzidine Amine (134 mg, 0.5 mmol), perylene-4-carboxylic acid (174 mg, L0 mmol) and HATU (380 mg, 1.0 mmol) were purified by reverse phase HPLC to provide Title compound (25 mg, 12%). iHNMRGOOMHACDsOD) 5 0.94 (m, 2H), 1.17 (m, 3H), 1.66 (m, 6H), 3.14 (d, J = 6.8 Hz, 2H), 7.58 (dd, J = 8.8, 2 · 4 Hz, 1H), 7.75 (d, > 2.4 Hz, 1H), 7.96 (m, 1H), 8.03 (m, 1H), 8.51 (m, 3H), 9.52 (s , 1H); MS (ESI) (M + H) + 423.1 · Example 67 N- [4-Gas-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -2-methoxy -1-carboxamidine

按照如實例51中步驟A之方法，使用二異丙基乙胺（127 毫克，1.0毫莫耳）、2-胺基-5·氣(環己基曱基)-苯甲醯胺（134 毫克，0.5毫莫耳）、2-甲氧基小萘甲酸(203毫克，1.0毫莫耳） 101539 -90- 200539856 及HATU (380毫克，1.0毫莫耳），藉由逆相HPLC純化後，提 供標題化合物（12毫克，5%)。iHNMRGOOMHACDsOD) 5 0.89 (m，2H)，1·17 (m，3H)，1.56 (m，1H)，1.69 (m，5H)，3.06 (d，J=6.4 Hz，2H)， 3.96 (s5 3H)5 7.36 (m, 1H), 7.47 (m, 2H), 7.55 (dd, J=9.2, 2.4 Hz, 1H), 7.67 (d，J=2.4 Hz，1H)，7·84 (m，2H)，7.98 (d，J=9.2 Hz，1H)，8.65 (d，J=8.8 Hz， 1H)，8·69 (m，1H) ; MS (ESI) (M+H)+451.1. 實例68 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-吡啶羧醯胺Following the procedure of Step A in Example 51, using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5 · (cyclohexylfluorenyl) -benzamide (134 mg, 0.5 mmol), 2-methoxy-naphthoic acid (203 mg, 1.0 mmol) 101539 -90- 200539856 and HATU (380 mg, 1.0 mmol), after purification by reverse phase HPLC, the title is provided Compound (12 mg, 5%). iHNMRGOOMHACDsOD) 5 0.89 (m, 2H), 1.17 (m, 3H), 1.56 (m, 1H), 1.69 (m, 5H), 3.06 (d, J = 6.4 Hz, 2H), 3.96 (s5 3H) 5 7.36 (m, 1H), 7.47 (m, 2H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.84 (m, 2H), 7.98 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.69 (m, 1H); MS (ESI) (M + H) +451.1. Example 68 N- [ 4-amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-pyridinecarboxamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯曱醯胺（134毫克，0·5 毫莫耳）及2_吡啶羰基氣鹽酸鹽（135毫克，0.75毫莫耳），提 供標題化合物（78 毫克，42%)。1H NMR (400 MHz，CDC13) 6 1.00 (m，2H)，1.21 (m，3H)，1·56 (m，1H)，1·74 (m，5H)，3·30 (m，2H)，6·13 (brs， 1H)，7.44 (m，3H)，7.86 (m，1H)，8.22 (dd，J=8.0,1.2 Hz，1H)，8·73 (m，1H)， 8·78 (d，J=9_2 Hz，1H)，12.57 (brs，1H) ; MS (ESI) (Μ+Η)+372·1· 實例69 N-[4-氣基冬[[(環己基甲基）胺基]羰基]苯基]-2-氟基-3_(三氟甲 基）-苯甲醯胺 101539 -91- 200539856Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -phenylhydrazine (134 mg, 0.5 mmol) and 2-pyridylcarbonyl gas hydrochloride (135 mg, 0.75 mmol) to provide the title compound (78 mg, 42%). 1H NMR (400 MHz, CDC13) 6 1.00 (m, 2H), 1.21 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.30 (m, 2H), 6.13 (brs, 1H), 7.44 (m, 3H), 7.86 (m, 1H), 8.22 (dd, J = 8.0, 1.2 Hz, 1H), 8.73 (m, 1H), 8.78 ( d, J = 9_2 Hz, 1H), 12.57 (brs, 1H); MS (ESI) (Μ + Η) + 372 · 1 · Example 69 N- [4-Gasyldong [[(cyclohexylmethyl) amine Yl] carbonyl] phenyl] -2-fluoro-3_ (trifluoromethyl) -benzylamine 101539 -91- 200539856

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（134毫克，0.5 毫莫耳）及2-氟基-3-(三氟甲基）苯甲醯氣（177毫克，0.75毫莫 耳），提供標題化合物（84毫克，37%)。eNMRGOOMHz'DC^) 5 1.02 (m，2H)，1.22 (m，3H)，1_58 (m，1H)，1.77 (m，5H)，3·30 (m，2H)，6.19 (brs, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.49 (d, J=9.2 Hz, 1H), 7.78 (m5 1H)，8.18 (m，1H)，8.69 (d，J=9.2 Hz，1H)，11·64 (brs，1H); MS (ESI) (M+H)+457.0. 實例70 N-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-2,3-二氟-苯甲醯胺Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide (134 mg, 0.5 mmol) and 2-fluoro-3- (trifluoromethyl) benzidine (177 mg, 0.75 mmol) to provide the title compound (84 mg, 37%). eNMRGOOMHz'DC ^) 5 1.02 (m, 2H), 1.22 (m, 3H), 1_58 (m, 1H), 1.77 (m, 5H), 3.30 (m, 2H), 6.19 (brs, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.78 (m5 1H), 8.18 (m, 1H), 8.69 (d, J = 9.2 Hz, 1H), 11.64 (brs, 1H); MS (ESI) (M + H) +457.0. Example 70 N- [4-Gamo-2-[[(cyclohexylfluorenyl) amino]] Carbonyl] phenyl] -2,3-difluoro-benzamide

按照如實例53之方法，使用二異丙基乙胺（190毫克，1.5 毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯甲醯胺（134毫克，0.5 毫莫耳）及2,3-二氟·苯甲醯氣（132毫克，0.75毫莫耳），提供 標題化合物（17 毫克，8%)。1H NMR (400 MHz，CDC13) δ 1.02 (m， 2Η)，1·22 (m，3Η)，1.58 (m，1Η)，1.78 (m，5Η)，3·30 (m，2Η)，6·19 (brs，1Η)， 101539 -92- 200539856 7·21 (m，1H)，7.34 (m，1H)，7.45 (s，1H)，7.48 (m，1H)，7.74 (m，1H)，8.71 (d， J=8.8 Hz，1H)，11.64 (brs，1H) ; MS (ESI) (M+H)+407.0· 實例71 3-氣_N-[4-氣基-2-[[(環己基甲基)胺基M基]苯基]-2-氟-苯甲醯胺Following the procedure as in Example 53, diisopropylethylamine (190 mg, 1.5 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide (134 mg, 0.5 mmol) and 2,3-difluoro · benzidine gas (132 mg, 0.75 mmol) to provide the title compound (17 mg, 8%). 1H NMR (400 MHz, CDC13) δ 1.02 (m, 2Η), 1.22 (m, 3Η), 1.58 (m, 1Η), 1.78 (m, 5Η), 3.30 (m, 2Η), 6 · 19 (brs, 1Η), 101539 -92- 200539856 7.21 (m, 1H), 7.34 (m, 1H), 7.45 (s, 1H), 7.48 (m, 1H), 7.74 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 11.64 (brs, 1H); MS (ESI) (M + H) + 407.0 · Example 71 3- 气 _N- [4- 气 基 -2-[[(环Hexylmethyl) amino M] phenyl] -2-fluoro-benzamide

按照如實例53之方法，使用二異丙基乙胺（127毫克，1.0 毫莫耳）、2-胺基-5-氣-N-(環己基甲基)-苯曱醯胺（50毫克，0.19 毫莫耳）及2-氟基-3-氣-苯甲醯氣(58毫克，0.3毫莫耳），提供 標題化合物（14 毫克，18%)。iHNMRGOOMHz'DClOS 1.02 (m，2H)，1·23 (m，3H)，1.56 (m，1H)，1.75 (m，5H)，3.30 (m，2H)，6.19 (brs， 1H)，7.22 (m，2H)，7·46 (s，2H)，7.87 (m，1H)，8.69 (d，J=8.8 Hz，1H)，11.59 (brs，1H) ; MS (ESI) (M+H)+423.0· 實例72 N_[4·氣基-2-[[(環己基曱基）胺基]羰基]苯基]-2,3-二甲基-苯曱 醯胺Following the procedure as in Example 53, diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -phenylhydrazine (50 mg, 0.19 mmol) and 2-fluoro-3-gas-benzidine gas (58 mg, 0.3 mmol) to provide the title compound (14 mg, 18%). iHNMRGOOMHz'DClOS 1.02 (m, 2H), 1.23 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 3.30 (m, 2H), 6.19 (brs, 1H), 7.22 (m , 2H), 7.46 (s, 2H), 7.87 (m, 1H), 8.69 (d, J = 8.8 Hz, 1H), 11.59 (brs, 1H); MS (ESI) (M + H) +423.0 · Example 72 N_ [4 · Gas-2--2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -2,3-dimethyl-phenylhydrazine

按照如實例53之方法，使用二異丙基乙胺（127毫克，1.0 101539 -93- 200539856 毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（50毫克，0.19 毫莫耳）及氯化2,3-二甲苯甲醯（51毫克，0.3毫莫耳），提供 標題化合物（22 毫克，30%)。1H NMR (400 MHz，CDC13 ) 5 0.96 (m， 2H)，1.21 (m，3H)，1·56 (m，1H)，1.75 (m，5H)，2·32 (s，3H)，2·39 (s，3H)， 3·24 (m，2H)，6.20 (brs，1H)，7.16 (m，1H)，7.24 (m，1H)，7.36 (d，J=7.6 Hz， 1H)，7.43 (s，1H)，7.48 (d，J=8.8 Hz，1H)，8.78 (d，J=8.8 Hz，1H)，1U4 (brs， 1H) ； MS (ESI) (M+H)+399.0. 實例73Following the procedure as in Example 53, diisopropylethylamine (127 mg, 1.0 101539 -93- 200539856 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzidine was used Amine (50 mg, 0.19 mmol) and 2,3-dimethyltoluene chloride (51 mg, 0.3 mmol) provided the title compound (22 mg, 30%). 1H NMR (400 MHz, CDC13) 5 0.96 (m, 2H), 1.21 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 2.32 (s, 3H), 2 · 39 (s, 3H), 3.24 (m, 2H), 6.20 (brs, 1H), 7.16 (m, 1H), 7.24 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 8.78 (d, J = 8.8 Hz, 1H), 1U4 (brs, 1H); MS (ESI) (M + H) +399.0. Examples 73

N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-3-氟-2-(三氟甲 基）-苯甲醯胺N- [4-Gamo-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3-fluoro-2- (trifluoromethyl) -benzamide

按照如實例53之方法，使用二異丙基乙胺（127毫克，1.0 毫莫耳）、2-胺基-5-氣(環己基甲基）-苯甲醯胺（50毫克，0.19 毫莫耳）及3-氟基-2-(三氟甲基）苯甲醯氣（68毫克，0.3毫莫 耳），提供標題化合物（20毫克，15%)。1 HNMR(400 MHz，CDC13) 5 0.99 (m，2H)，1.24 (m，3H)，1.56 (m，1H)，1·75 (m，5H)，3.24 (m，2H)， 6.22 (brs，1H)，7.30 (m，1H)，7.36 (d，J=7.6 Hz，1H)，7.45 (s，1H)，7.50 (dd， J=9.2, 2.4 Hz, 1H)，7·60 (m，1H)，8.67 (d，J=9.2 Hz，1H)，11.31 (brs，1H); MS (ESI) (M+H)+457.0. 101539 -94- 200539856 實例74 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,2-二氟-1，3_苯并 二氧伍圜烯-4-羧醯胺Following the procedure as in Example 53, using diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas (cyclohexylmethyl) -benzamide (50 mg, 0.19 mmol) Ear) and 3-fluoro-2- (trifluoromethyl) benzidine gas (68 mg, 0.3 mmol) provided the title compound (20 mg, 15%). 1 HNMR (400 MHz, CDC13) 5 0.99 (m, 2H), 1.24 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 3.24 (m, 2H), 6.22 (brs, 1H), 7.30 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.50 (dd, J = 9.2, 2.4 Hz, 1H), 7.60 (m, 1H ), 8.67 (d, J = 9.2 Hz, 1H), 11.31 (brs, 1H); MS (ESI) (M + H) +457.0. 101539 -94- 200539856 Example 74 N- [4-Gas-2- [[(Cyclohexylmethyl) amino] carbonyl] phenyl] -2,2-difluoro-1,3-benzodioxolene-4-carboxamide

按照如實例53之方法，使用二異丙基乙胺（127毫克，1.0 毫莫耳）、2-胺基-5-氣-N-(環己基曱基)-苯甲醯胺（50毫克，0.19 毫莫耳）及2,2-二氟-1，3-苯并二氧伍圜烯-4-氣化碳醯（66毫克， 0·3毫莫耳），提供標題化合物（13毫克，10%)。WNMR (400 MHz, CDC13 ) 5 1.02 (m, 2H)? 1.23 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H)，3.30 (m，2H)，6·18 (brs，1H)，7.22 (m，2H)，7.47 (s，2H)，7·68 (dd，J=6.8, 2·4 Hz，1H)，8.71 (d，J=8.8 Hz，1H)，11.66 (brs，1H) ； MS (ESI) (M+H)+ 451.0.Following the procedure as in Example 53, diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas-N- (cyclohexylfluorenyl) -benzamide (50 mg, 0.19 mmol) and 2,2-difluoro-1,3-benzodioxolene-4-gasocarbon (66 mg, 0.3 mmol), to provide the title compound (13 mg, 10%). WNMR (400 MHz, CDC13) 5 1.02 (m, 2H)? 1.23 (m, 3H), 1.56 (m, 1H), 1.75 (m, 5H), 3.30 (m, 2H), 6.18 (brs, 1H ), 7.22 (m, 2H), 7.47 (s, 2H), 7.68 (dd, J = 6.8, 2.4 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 11.66 (brs, 1H); MS (ESI) (M + H) + 451.0.

實例75 N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-6-氟基-4H-1，3-苯 并二氧陸圜烯-8-羧醯胺Example 75 N- [4-Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -6-fluoro-4H-1,3-benzodioxolene-8- Carboxamide

101539 -95- 200539856 按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，〇·4毫莫耳）、2-胺基-5-氯-N-(環己基甲基）-苯甲醯胺（5〇毫 克，0.19毫莫耳）、6-亂基-4Η-1，3-苯并二氧陸圜烯各羧酸(60 毫克，0.3毫莫耳）及HATU (152毫克，0.4毫莫耳），藉由逆相 HPLC純化後，提供標題化合物（39毫克，47%)。WNMR (400 MHz, CDC13 ) (5 1.01 (m, 2H), 1.23 (m, 3H), 1.56 (m, 1H), 1.76 (m, 5H), 3.26 (m, 2H), 4.97 (s, 2H), 5.50 (s, 2H), 6.06 (brs, 1H), 6.86 (m5 1H), 7.40 (s51H), 7.44 (dd, J=7.6, 1.2 Hz? 1H), 7.78 (dd51=7.6, 1.2 Hz, 1H), 8.66 (d，J=9.2 Hz，1H)，11.61 (brs，1H) ; MS (ESI) (M+H)+447.0· 實例76 N_[4-氣基·2-[[(環己基甲基）胺基]羰基]苯基]_2-甲基-3-(三氟甲 基）-苯甲醯胺101539 -95- 200539856 According to the method in step A of Example 51, using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-chloro-N- (cyclohexylmethyl) )-Benzamidine (50 mg, 0.19 mmol), 6-ranyl-4, -1,3-benzodioxolene carboxylic acid (60 mg, 0.3 mmol) and HATU ( 152 mg, 0.4 mmol), and purified by reverse phase HPLC to provide the title compound (39 mg, 47%). WNMR (400 MHz, CDC13) (5 1.01 (m, 2H), 1.23 (m, 3H), 1.56 (m, 1H), 1.76 (m, 5H), 3.26 (m, 2H), 4.97 (s, 2H) , 5.50 (s, 2H), 6.06 (brs, 1H), 6.86 (m5 1H), 7.40 (s51H), 7.44 (dd, J = 7.6, 1.2 Hz? 1H), 7.78 (dd51 = 7.6, 1.2 Hz, 1H ), 8.66 (d, J = 9.2 Hz, 1H), 11.61 (brs, 1H); MS (ESI) (M + H) + 447.0 · Example 76 N_ [4-Gas · 2-[[(cyclohexylmethyl ) Amino] carbonyl] phenyl] _2-methyl-3- (trifluoromethyl) -benzidine

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0.4毫莫耳）、2-胺基-5-氯(環己基甲基）-苯甲醯胺（50毫 克，0_19毫莫耳）、2-甲基-3-(三氟甲基)-苯曱酸（61毫克，0.3 毫莫耳）及HATU(152毫克，0·4毫莫耳），藉由逆相HPLC純化 後，提供標題化合物（20毫克，23%)。WnMRGOOMHaCDCIJ 5 0.99 (m，2H)，1.22 (m，3H)，1·56 (m，1H)，1.74 (m，5H)，2·59 (s，3H)，3·25 (m，2Η)，6.25 (brs，1Η)，7·40 (m，1Η)，7.45 (s，1Η)，7·51 (dd，J=8.8, 2·4 Ηζ， 101539 -96- 200539856 1H)，7.67 (d，J=7.6 Ηζ，1Η)，7·73 (d，J=7.6 Ηζ，1Η)，8·77 (d，J=7.6 Hz，1H)， 11.36 (brs, 1H) ； MS (ESI) (M+H)+453.0. 實例77 3-氣-N-[4-氣基-2-[[(環己基甲基）胺基機基]苯基]-2-甲基_苯甲 醯胺Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-chloro (cyclohexylmethyl) -benzamide (50 mg, 0-19 mol), 2-methyl-3- (trifluoromethyl) -phenylarsinic acid (61 mg, 0.3 mol), and HATU (152 mg, 0.4 mol) After HPLC purification, the title compound (20 mg, 23%) was provided. WnMRGOOMHaCDCIJ 5 0.99 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 2.59 (s, 3H), 3.25 (m, 2Η), 6.25 (brs, 1Η), 7.40 (m, 1Η), 7.45 (s, 1Η), 7.51 (dd, J = 8.8, 2.4 4ζ, 101539 -96- 200539856 1H), 7.67 (d, J = 7.6 Ηζ, 1Η), 7.73 (d, J = 7.6 Ηζ, 1Η), 8.77 (d, J = 7.6 Hz, 1H), 11.36 (brs, 1H); MS (ESI) (M + H) +453.0. Example 77 3-Gas-N- [4-Gasyl-2-[[(cyclohexylmethyl) aminomethyl] phenyl] -2-methyl-benzidine

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，〇·4毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（50 毫克，〇·19毫莫耳）、2-甲基-3-氣-苯甲酸(51毫克，0.3毫莫耳） 及HATU (152毫克，0.4毫莫耳），藉由逆相HPLC純化後，提 供標題化合物（10 毫克，13%)。1H NMR (400 MHz，CDC13) 5 0.97 (m，2H)，1.21 (m，3H)，1.56 (m，1H)，1_72 (m，5H)，2.50 (s，3H)，3.22 (m，2H)， 6.22 (brs，1H)，7.20 (m，2H)，7.42 (m，3H)，8.73 (d，J=8_8 Hz，1H)，11.29 (brs, 1H) ； MS (ESI) (M+H)+419.0. 實例78 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,3-二曱氧基-苯 曱醯胺 101539 -97- 200539856Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzidine Amine (50 mg, 0.19 mmol), 2-methyl-3-gas-benzoic acid (51 mg, 0.3 mmol) and HATU (152 mg, 0.4 mmol) by reverse phase HPLC After purification, the title compound (10 mg, 13%) was provided. 1H NMR (400 MHz, CDC13) 5 0.97 (m, 2H), 1.21 (m, 3H), 1.56 (m, 1H), 1_72 (m, 5H), 2.50 (s, 3H), 3.22 (m, 2H) , 6.22 (brs, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 8.73 (d, J = 8_8 Hz, 1H), 11.29 (brs, 1H); MS (ESI) (M + H) +419.0. Example 78 N- [4-Amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2,3-dimethoxy-phenylhydrazine 101539 -97- 200539856

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0·4毫莫耳）、2-胺基-5-氣(環己基曱基）-苯甲醯胺（50 毫克，0.19毫莫耳）、2,3-二曱氧基-苯甲酸(55毫克，0·3毫莫 耳）及HATU (152毫克，0.4毫莫耳），藉由逆相HPLC純化後， 提供標題化合物（20毫克，25%)。iHNMRGOOMHACDC^)^ 0.99 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.27 (m, 2H), 3.91 (s, 3H), 4.02 (s, 3H), 6.12 (brs, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.13 (m5 1H), 7.40 (s3 1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H)5 7.65 (dd, J=8.0, 1.6 Hz, 1H), 8.61 (d，J=8.8 Hz, 1H)，11.54 (brs, 1H) ; MS (ESI) (M+H)+431.0· 實例79 N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-3-甲氧基-2-甲基-Following the procedure of Step A in Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-gas (cyclohexylfluorenyl) -benzamide (50 Mg, 0.19 mmoles), 2,3-dioxo-benzoic acid (55 mg, 0.3 mmoles) and HATU (152 mg, 0.4 mmoles), after purification by reverse phase HPLC, Provided the title compound (20 mg, 25%). iHNMRGOOMHACDC ^) ^ 0.99 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.27 (m, 2H), 3.91 (s, 3H), 4.02 (s, 3H), 6.12 (brs, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.13 (m5 1H), 7.40 (s3 1H), 7.44 (dd, J = 9.2, 2.4 Hz, 1H) 5 7.65 ( dd, J = 8.0, 1.6 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 11.54 (brs, 1H); MS (ESI) (M + H) + 431.0 · Example 79 N- [4- Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3-methoxy-2-methyl-

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0.4毫莫耳）、2-胺基-5-氣(環己基甲基）-苯甲醯胺（50 毫克，0.19毫莫耳）、2-甲基-3-甲氧基-苯甲酸(50毫克，0.3毫 101539 -98- 200539856 莫耳）及HATU (152毫克，0·4毫莫耳），藉由逆相HPLC純化 後，提供標題化合物（15毫克，19%)。iHNMRGOOMHACDCD 5 0.99 (m，2H)，1·24 (m，3H)，1.56 (m，1H)，1·77 (m，5H)，2.36 (s，3H)，3.24 (m, 2H)5 3.86 (s5 3H), 6.22 (brs, 1H), 6.93 (d3 J=8.0 Hz, 1H), 7.14 (d, J=7.2 Hz，1H)，7.23 (d，J=8.0 Hz，1H)，7·43 (s，1H)，7.48 (dd，J=9.2, 2·4 Hz，1H)， 8.77 (d，J=9.2 Hz，1H)，1U6 (brs，1H) ; MS (ESI) (Μ+Η)+415·0· 實例80 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-5-異喹啉羧醯胺Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-gas (cyclohexylmethyl) -benzamide (50 mg, 0.19 mmol), 2-methyl-3-methoxy-benzoic acid (50 mg, 0.3 mmol 101539 -98- 200539856 Mol) and HATU (152 mg, 0.4 mmol) After phase HPLC purification, the title compound (15 mg, 19%) was provided. iHNMRGOOMHACDCD 5 0.99 (m, 2H), 1.24 (m, 3H), 1.56 (m, 1H), 1.77 (m, 5H), 2.36 (s, 3H), 3.24 (m, 2H) 5 3.86 ( s5 3H), 6.22 (brs, 1H), 6.93 (d3 J = 8.0 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.43 ( s, 1H), 7.48 (dd, J = 9.2, 2.4 Hz, 1H), 8.77 (d, J = 9.2 Hz, 1H), 1U6 (brs, 1H); MS (ESI) (Μ + Η) + 415 · 0 · Example 80 N- [4-Amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -5-isoquinolinecarboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0.4毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（50 毫克，〇·19毫莫耳）、異喳啉-5-羧酸(52毫克，0.3毫莫耳）及 φ HATU(152毫克，0.4毫莫耳），藉由逆相HPLC純化後，提供 標題化合物（18 毫克，23%)。1H NMR (400 MHz，CDC13) 6 0.99 (m， 2H)，1.22 (m，3H)，1.56 (m，1H)，1.74 (m，5H)，3·25 (m，2H)，6·25 (brs，1H)， 7.46 (s，1H)，7.54 (m，1H)，7.68 (m，1H)，8.12 (m，2H)，8.40 (m，1H)，8.62 (d， J=8.0 Hz, 1H)5 8.86 (d5 J=8.0 Hz, 1H), 9.32 (s5 1H), 11.76 (brs, 1H)； MS (ESI) (M+H)+422.0. 101539 -99- 200539856 實例81 6·氣-N_[4_氯基-2-[[(環己基甲基）胺基]幾基]苯基]-2-氟基-3-甲 基-苯甲醯胺Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide ( 50 mg, 0.19 mmoles), isoxoline-5-carboxylic acid (52 mg, 0.3 mmoles) and φ HATU (152 mg, 0.4 mmoles), after purification by reverse phase HPLC, provided Title compound (18 mg, 23%). 1H NMR (400 MHz, CDC13) 6 0.99 (m, 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.25 (m, 2H), 6.25 ( brs, 1H), 7.46 (s, 1H), 7.54 (m, 1H), 7.68 (m, 1H), 8.12 (m, 2H), 8.40 (m, 1H), 8.62 (d, J = 8.0 Hz, 1H ) 5 8.86 (d5 J = 8.0 Hz, 1H), 9.32 (s5 1H), 11.76 (brs, 1H); MS (ESI) (M + H) +422.0. 101539 -99- 200539856 Example 81 6 · Gas-N_ [4-Chloro-2--2-[[(cyclohexylmethyl) amino] jiki] phenyl] -2-fluoroyl-3-methyl-benzamide

按照如實例53之方法，使用二異丙基乙胺（127毫克，1.0 毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（50毫克，0.19 毫莫耳）及2-氟基-6-氣基-3-甲基-苯甲酿氣（62毫克，0.3毫莫 耳），提供標題化合物（43毫克，53°/❶）。iHNMRGOOMHiCDCU) δ 0.99 (m, 2H), 1.21 (m, 3H), 1.56 (m5 1H), 1.76 (m, 5H), 2.27 (s, 3H), 3.24 (m, IK), 6.22 (brs, 1H), 7.15 (m, 2H), 7.44 (s, 1H), 7.50 (dd5 J=8.8, 2.0 Hz, 1H), 8.75 (d, J=9.2 Hz? 1H), 11.20 (brs, 1H) ； MS (ESI) (M+H)+437.0. 實例82 # 2-氣-N-[4-氣基-2_[[(環己基甲基）胺基]幾基]苯基]-3-(三氟甲 基）-苯甲醯胺Following the procedure as in Example 53, diisopropylethylamine (127 mg, 1.0 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide (50 mg, 0.19 mmol) and 2-fluoro-6-amino-3-methyl-benzyl gas (62 mg, 0.3 mmol) to provide the title compound (43 mg, 53 ° / ❶). iHNMRGOOMHiCDCU) δ 0.99 (m, 2H), 1.21 (m, 3H), 1.56 (m5 1H), 1.76 (m, 5H), 2.27 (s, 3H), 3.24 (m, IK), 6.22 (brs, 1H) , 7.15 (m, 2H), 7.44 (s, 1H), 7.50 (dd5 J = 8.8, 2.0 Hz, 1H), 8.75 (d, J = 9.2 Hz? 1H), 11.20 (brs, 1H); MS (ESI ) (M + H) +437.0. Example 82 # 2-Gas-N- [4-Gasyl-2 _ [[(Cyclohexylmethyl) amino] Jinyl] phenyl] -3- (trifluoromethyl ) -Benzamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0.4毫莫耳）、2-胺基-5-氯(環己基曱基)-苯甲醢胺（5〇毫 101539 -100- 200539856 克，0·19毫莫耳）、2-氯基-3-(三氟甲基）-苯甲酸(69毫克，0.3 毫莫耳）及HATU (152毫克，0.4毫莫耳），藉由逆相HPLC純化 後，提供標題化合物（12毫克，14%)。iHNMRGOOMHiCDCb) δ 0.99 (m5 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.25 (m, 2H), 6.25 (brs, 1H)5 7.53 (m5 3H), 7.74 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.75 (d, J=9.2 Hz, 1H), 11.42 (brs, 1H) ； MS (ESI) (M+H)+473.0. 實例83 N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]_5_喹啉羧醯胺Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-chloro (cyclohexylfluorenyl) -benzamide (50 mmol) 101539 -100- 200539856 g, 0.19 mmoles), 2-chloro-3- (trifluoromethyl) -benzoic acid (69 mg, 0.3 mmoles) and HATU (152 mg, 0.4 mmoles) ), After purification by reverse phase HPLC, provided the title compound (12 mg, 14%). iHNMRGOOMHiCDCb) δ 0.99 (m5 2H), 1.22 (m, 3H), 1.56 (m, 1H), 1.74 (m, 5H), 3.25 (m, 2H), 6.25 (brs, 1H) 5 7.53 (m5 3H), 7.74 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.75 (d, J = 9.2 Hz, 1H), 11.42 (brs, 1H); MS (ESI) (M + H) +473.0. Example 83 N- [4-Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -5_quinolinecarboxamide

按照如實例51中步驟A之方法，使用二異丙基乙胺（51毫 克，0.4毫莫耳）、2-胺基-5-氣-N-(環己基甲基）-苯甲醯胺（50 毫克，0.19毫莫耳）、喳啉-5-羧酸(52毫克，0.3毫莫耳）及HATU • (152毫克，0.4毫莫耳），藉由逆相HPLC純化後，提供標題化 合物（23 毫克，29%)。1H NMR (400 MHz，CD3 0D) δ .98 (m，2H)，1.22 (m，3Η)，1.74 (m，6Η)，3·17 (d，J=6.8 Ηζ，2Η)，7.60 (d，J=6.8 Ηζ，1Η)，7·78 (s，1H)，7.90 (m，1H)，8·10 (m，1H)，8.19 (d，J=6.80 Hz，1H)，8.31 (d，J=8.4 Hz, 1H), 8.60 (d, J=8.8 Hz, 1H), 9.11 (s, 1H), 9.37 (d, J=8.8 Hz5 1H)； MS (ESI) (M+H)+422.0. 實例84 N-[2-[[(環己基曱基）胺基]幾基H-甲氧苯基]-1-莕羧醯胺 101539 -101- 200539856Following step A of Example 51 using diisopropylethylamine (51 mg, 0.4 mmol), 2-amino-5-gas-N- (cyclohexylmethyl) -benzamide ( 50 mg, 0.19 mmoles), perylene-5-carboxylic acid (52 mg, 0.3 mmoles) and HATU • (152 mg, 0.4 mmoles), after purification by reverse phase HPLC, the title compound ( 23 mg, 29%). 1H NMR (400 MHz, CD3 0D) δ .98 (m, 2H), 1.22 (m, 3Η), 1.74 (m, 6Η), 3.17 (d, J = 6.8 Ηζ, 2Η), 7.60 (d, J = 6.8 Ηζ, 1Η), 7.78 (s, 1H), 7.90 (m, 1H), 8.10 (m, 1H), 8.19 (d, J = 6.80 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H), 9.11 (s, 1H), 9.37 (d, J = 8.8 Hz5 1H); MS (ESI) (M + H) +422.0. Examples 84 N- [2-[[(Cyclohexylfluorenyl) amino] amino] Hexyl H-methoxyphenyl] -1-fluorenecarboxamide 101539 -101- 200539856

步驟A. N-[2-[[(環己基甲基）胺基]幾基l·4·甲氧苯基]小莕羧醯胺Step A. N- [2-[[(Cyclohexylmethyl) amino] aminol · 4 · methoxyphenyl] carboxamide

按照如實例53之方法，使用二異丙基乙胺（1毫升）、2-胺 基-5-曱氧基(環己基甲基）-苯甲醯胺（5.17毫莫耳，關於其 製備可參閱步驟B)及氯化1-萘醯（1.14毫升，5.68毫莫耳），提 供標題化合物（72 毫克，4%)。1HNMR(400MHz，DMSO-D6) 5 0.81 (d? J=11.72 Hz, 2H) 1.06 (m, 3H) 1.58 (m, 6H) 3.00 (t, J=6.35 Hz, 2H) 3.78 (s, 3H) 7.15 (dd, J=8.98,2.93 Hz, 1H) 7.29 (d, J=2.93 Hz, 1H) 7.56 (m, 3H) 7.75 (dd，J=7.03, 0.98 Hz，1H) 7.97 (dd，J=6.15, 3·42 Hz，1H) 8.05 (d， 8.20 Hz, 1H) 8.30 (dd, J=6.35, 3.61 Hz, 1H) 8.46 (d5 J=8.98 Hz, 1H) 8.73 (s, 1H) 11.64 (s，1H).MS (ESI) (M+H)+417.1. 步驟B· 2-胺基-5-甲氧基_N-(環己基曱基）_苯甲醯胺According to the method as in Example 53, using diisopropylethylamine (1 ml), 2-amino-5-fluorenyloxy (cyclohexylmethyl) -benzamide (5.17 mmol), its preparation can be See step B) and 1-naphthalene chloride (1.14 ml, 5.68 mmol) to provide the title compound (72 mg, 4%). 1HNMR (400MHz, DMSO-D6) 5 0.81 (d? J = 11.72 Hz, 2H) 1.06 (m, 3H) 1.58 (m, 6H) 3.00 (t, J = 6.35 Hz, 2H) 3.78 (s, 3H) 7.15 (dd, J = 8.98, 2.93 Hz, 1H) 7.29 (d, J = 2.93 Hz, 1H) 7.56 (m, 3H) 7.75 (dd, J = 7.03, 0.98 Hz, 1H) 7.97 (dd, J = 6.15, 3.42 Hz, 1H) 8.05 (d, 8.20 Hz, 1H) 8.30 (dd, J = 6.35, 3.61 Hz, 1H) 8.46 (d5 J = 8.98 Hz, 1H) 8.73 (s, 1H) 11.64 (s, 1H ) .MS (ESI) (M + H) +417.1. Step B · 2-Amino-5-methoxy_N- (cyclohexylfluorenyl) _benzidine

KK

按照如實例51中步驟B之方法，使用二異丙基乙胺（1毫 101539 •102- 200539856 升）、5-曱氧基-伊沙東（isatonic)酸酐（1·〇克，5.17毫莫耳）、環 己基甲胺（673微升，5.17毫莫耳），提供標題化合物，其係 直接使用於步驟A。 實例85 N-(3-甲氧基-2-{[(2-六氫吡啶-1-基乙基）胺基]羰基}苯基）-1-莕 甲醯胺Following the procedure as in step B in Example 51, using diisopropylethylamine (1 mmol 101539 • 102-200539856 liters), 5-methoxy-isatonic anhydride (1.0 g, 5.17 mmol) Ear), cyclohexylmethylamine (673 μl, 5.17 mmol), to provide the title compound, which was used directly in step A. Example 85 N- (3-Methoxy-2-{[((2-hexahydropyridine-1-ylethyl) amino] carbonyl} phenyl) -1-fluorene formamidine

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基）-4Η·3，1-苯并哼畊-4-酮（100毫克，0.33毫莫耳）與（2-六氫吡 啶小基乙基）胺（128毫克，1.0毫莫耳），提供標題化合物（79 毫克，56%)。1HNMR(400MHz，CDC13) 5 1.47(m，2H)，1.58(m，4H)， 2.41 (m，4H)，2.48 (m，2H)，3.44 (m，2H)，3.98 (s，3H)，6.77 (dd，J=8.4,1.2 Hz，1H)，7.53 (m，4H)，7·87 (dd，J=7.2,1.2 Hz，2H)，7.94 (d, J=8.4 Hz，1H)， 8.50 (brs，1H)，8.54 (d，J=8.0 Hz，1H)，8·61 (dd，J=8.4,1·2 Hz，1H)，12·79 (brs，1H) ; MS (ESI) (M+H)+432.0· 實例86 N-(2-{[(l，4-二氧陸圜-2-基曱基）胺基]羰基}_3-曱氧苯基)-1-莕曱 醯胺 101539 -103- 200539856Following step A in Example 14 using 5-methoxy-2- (1-fluorenyl) -4fluorene · 3,1-benzohumen-4-one (100 mg, 0.33 mmol) and (2-Hexahydropyridylethyl) amine (128 mg, 1.0 mmol) provided the title compound (79 mg, 56%). 1HNMR (400MHz, CDC13) 5 1.47 (m, 2H), 1.58 (m, 4H), 2.41 (m, 4H), 2.48 (m, 2H), 3.44 (m, 2H), 3.98 (s, 3H), 6.77 (dd, J = 8.4, 1.2 Hz, 1H), 7.53 (m, 4H), 7.87 (dd, J = 7.2, 1.2 Hz, 2H), 7.94 (d, J = 8.4 Hz, 1H), 8.50 ( brs, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.61 (dd, J = 8.4, 1.2 Hz, 1H), 12 · 79 (brs, 1H); MS (ESI) (M + H) + 432.0 · Example 86 N- (2-{[((l, 4-dioxolan-2-ylfluorenyl) amino] carbonyl} _3-fluorenylphenyl) -1-fluorenamine 101539 -103- 200539856

按照如實例14中步驟A之方法，使用5-甲氧基·2·(1-莕 基)-4Η-3，1-苯并嘮畊斗酮（100毫克，0.33毫莫耳）與（1，4·二氧陸 圜-2-基甲基）胺（117毫克，1.0毫莫耳），提供標題化合物（94 毫克，68%)。iHNMR(400 MHz，CDC13) 5 3.37 (m，2H)，3.59(m，2Η)， 3.78 (m, 5H), 3.97 (s, 3H), 6.79 (d, J=8.4 Hz, 1H), 7.53 (m, 4H), 7.86 (m, 2H), 7.95 (d, J=8_4 Hz，1H)，8.20 (brs，1H), 8.53 (d，J=8.0 Hz，1H)，8.61 (dd，J= 8·4, 0·8 Hz，1H)，12.56 (brs，1H) ; MS (ESI) (M+H)+421.0· 實例87 N-(3-甲氧基_2-{[(2-嗎福啉-4-基乙基）胺基]羰基}苯基）-ΐ·莕甲 醯胺Following the procedure as in step A in Example 14, 5-methoxy · 2 · (1-fluorenyl) -41--3,1-benzopyrene pentone (100 mg, 0.33 mmol) and (1 4,4-Dioxolane-2-ylmethyl) amine (117 mg, 1.0 mmol) to provide the title compound (94 mg, 68%). iHNMR (400 MHz, CDC13) 5 3.37 (m, 2H), 3.59 (m, 2Η), 3.78 (m, 5H), 3.97 (s, 3H), 6.79 (d, J = 8.4 Hz, 1H), 7.53 ( m, 4H), 7.86 (m, 2H), 7.95 (d, J = 8_4 Hz, 1H), 8.20 (brs, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.61 (dd, J = 8 · 4, 0 · 8 Hz, 1H), 12.56 (brs, 1H); MS (ESI) (M + H) + 421.0 · Example 87 N- (3-methoxy_2-{[(2-morphol Phenyl-4-ylethyl) amino] carbonyl} phenyl) -fluorene

按照如實例14中步驟Α之方法，使用5-甲氧基-2-(1-莕 基)-4Η-3，1-苯并哼啡-4-酮（100毫克，0.33毫莫耳）與（2-嗎福啉-4-基乙基）胺（130毫克，1.0毫莫耳），提供標題化合物（112毫 克，78%)。iHNMRGOOMHz'DCb) 5 2.50(m，4H)，2.56(m，2H)， 3.49 (m，2H)，3.72 (m，4H)，3·99 (s，3H)，6·78 (dd，J=8.4,1·2 Hz，1H)，7·53 101539 200539856 (m，4H)，7·87 (m，2H)，7·95 (d，J=8.4 Ηζ，1Η)，8·41 (brs，1Η)，8·53 (d，J=7.6 Hz，1H)，8_61 (dd，J=8.4, 0.8 Hz，1H)，12.72 (brs，1H) ; MS (ESI) (M+H)+ 434.0. 實例88 N-(3-甲氧基-2-{[(2-四氫吡咯小基乙基）胺基]羰基}苯基）-1-莕 甲醯胺Following step A in Example 14, using 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1-benzohumin-4-one (100 mg, 0.33 mmol) and (2-morpholin-4-ylethyl) amine (130 mg, 1.0 mmol) provided the title compound (112 mg, 78%). iHNMRGOOMHz'DCb) 5 2.50 (m, 4H), 2.56 (m, 2H), 3.49 (m, 2H), 3.72 (m, 4H), 3.99 (s, 3H), 6.78 (dd, J = 8.4, 1.2 Hz, 1H), 7.53 101539 200539856 (m, 4H), 7.87 (m, 2H), 7.95 (d, J = 8.4 Ηζ, 1Η), 8.41 (brs, 1Η), 8.53 (d, J = 7.6 Hz, 1H), 8_61 (dd, J = 8.4, 0.8 Hz, 1H), 12.72 (brs, 1H); MS (ESI) (M + H) + 434.0. Example 88 N- (3-methoxy-2-{[((2-tetrahydropyrrole small ethyl) amino) carbonyl] phenyl) -1-methylformamide

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基）-4Η-3，1·苯并嘮畔-4-酮（100毫克，0.33毫莫耳）與（2_四氫吡 咯小基乙基）胺（114毫克，1.0毫莫耳），提供標題化合物（108 毫克，78%)。1HNMR(400 MHz，CDC13) 5 1.80(m，4Η)，2.54 (m，4H)， 2.65 (m，2H)，3.47 (m，2H)，3.92 (s，3H)，6_76 (d，J=8.0 Hz，1H)，7·52 (m， 4H)，7.87 (d，J=8.0 Hz，2H)，7.94 (d，J=8.4 Hz，1H)，8.46 (brs，1H)，8·54 (d， J=8.0 Hz，lH)，8.60 (d，J=8.0 Hz，lH), 12.71 (brs，lH) ; MS (ESI) (M+H)+ 418.0· 實例89 N-{3_曱氧基-2-[(四氫_2H-旅喃基胺基凍基]苯基}小莕甲醯胺Following step A in Example 14 using 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1 · benzofluoran-4-one (100 mg, 0.33 mmol) and (2-tetrahydropyrrole small ethyl) amine (114 mg, 1.0 mmol) provided the title compound (108 mg, 78%). 1HNMR (400 MHz, CDC13) 5 1.80 (m, 4Η), 2.54 (m, 4H), 2.65 (m, 2H), 3.47 (m, 2H), 3.92 (s, 3H), 6_76 (d, J = 8.0 Hz, 1H), 7.52 (m, 4H), 7.87 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.4 Hz, 1H), 8.46 (brs, 1H), 8.54 (d , J = 8.0 Hz, lH), 8.60 (d, J = 8.0 Hz, lH), 12.71 (brs, lH); MS (ESI) (M + H) + 418.0 · Example 89 N- {3_fluorenyloxy -2-[(tetrahydro_2H-branylaminofreezingyl] phenyl) berberamine

101539 -105- 200539856 按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基）-4Η-3，1_苯并吟哨1 -4_酮（100宅克’ 0.33毫莫耳）與四氳-2H-口辰 喃-4-胺（101毫克，1.0毫莫耳），提供標題化合物（98毫克， 74%)。1H NMR (400 MHz，CDC13) 5 1.56 (m，2H)，1·95 (m，2H)，3.50 (m， 2H)，3.92 (m，2H)，3.96 (s，3H)，4.16 (m，1H)，6.78 (d，J=7.6 Hz，1H)，7·53 (m，4H)，7·78 (m，1H)，7·87 (m，2H)，7.95 (d，J=8.4 Hz，1H)，8.53 (d，J=8.0 Hz，1H)，8.60 (d，J=8.0 Hz，1H)，12.50 (brs，1H) ; MS (ESI) (M+H)+405.0. 實例90 3-({[2-甲氧基-6-(1-莕甲醯基胺基）苯甲醯基]胺基}曱基）嗎福 啉-4-羧酸第三-丁酯101539 -105- 200539856 According to the method in step A of Example 14, using 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1-benzobenzone 1-4_one (100 gram) '0.33 millimolar) and tetrafluorene-2H-cholestan-4-amine (101 mg, 1.0 millimolar) provided the title compound (98 mg, 74%). 1H NMR (400 MHz, CDC13) 5 1.56 (m, 2H), 1.95 (m, 2H), 3.50 (m, 2H), 3.92 (m, 2H), 3.96 (s, 3H), 4.16 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.53 (m, 4H), 7.78 (m, 1H), 7.87 (m, 2H), 7.95 (d, J = 8.4 Hz , 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 12.50 (brs, 1H); MS (ESI) (M + H) +405.0. Example 90 3 -({[2-methoxy-6- (1-fluorenylmethylamino) benzamidine] amino} fluorenyl) morpholine-4-carboxylic acid tert-butyl ester

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-萘 春 基)-4Η-3，1-苯并吟_ -4-_ (100毫克，0.33毫莫耳）與3-(胺基甲 基）嗎福啉-4-羧酸第三-丁酯（216毫克，L0毫莫耳），提供標 題化合物（120 毫克，70%)。iHNMRpOOMHACDClO 5 1.30(s， 9H)，3·19 (m，1H)，3.44 (m，1H)，3·59 (m，1H)，3.80 (m，5H)，3·95 (s，3H)， 4.22 (m，1H)，6.75 (d，J=8.0 Hz，1H)，7.50 (m，4H)，7.88 (m，2H)，7.95 (d，J= 8.4 Hz，1H)，8.18 (brs，1H)，8.54 (d，J=8.0 Hz，1H)，8.64 (d，J=8.4 Hz，1H)， 12.80 (brs, 1H) ； MS (ESI) (M+H)+520.0. 101539 -106- 200539856 實例91 Ν-{2-[(1-氮雙環并[2·2·2]辛-3·基胺基）幾基]-3-甲氧苯基卜1_萘甲 醯胺Following step A in Example 14 using 5-methoxy-2- (1-naphthysyl) -4pyrene-3,1-benzoin_-4-_ (100 mg, 0.33 mmol) With 3- (aminomethyl) morpholine-4-carboxylic acid tert-butyl ester (216 mg, L0 mmol), the title compound (120 mg, 70%) was provided. iHNMRpOOMHACDClO 5 1.30 (s, 9H), 3.19 (m, 1H), 3.44 (m, 1H), 3.59 (m, 1H), 3.80 (m, 5H), 3.95 (s, 3H), 4.22 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H), 7.50 (m, 4H), 7.88 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 8.18 (brs, 1H ), 8.54 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 12.80 (brs, 1H); MS (ESI) (M + H) +520.0. 101539 -106- 200539856 Example 91 Ν- {2-[(1-Azabicyclo [2 · 2 · 2] oct-3 · ylamino) epiyl] -3-methoxyphenylbutan-1-naphthyridine

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基）·4Η-3，1-苯并哼畊斗酮（100毫克，0.33毫莫耳）與奎寧環-3-胺（126毫克，1.0毫莫耳），提供標題化合物（55毫克，39%)。 1H NMR (400 MHz, CD3 OD) δ 1.86 (m, 1H), 2.01 (m, 2H), 2.24 (m, 1H), 2.30 (m，1H)，3·18 (m，1H)，3.31 (m，4H)，3·72 (m，1H)，3·94 (s，3H)，4·40 (m，1H)，7.04 (d，J=8.4 Hz，1H)，7.53 (m，1H)，7·56 (m，4H)，7.79 (d，J=6.8 Hz, 1H), 7.95 (m, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.34 (m, 1H)； MS (ESI) (M+H)+430.2. 實例92 N-(3-甲氧基-2-{[(嗎福啉-3-基甲基)胺基]羰基}苯基）小莕甲醯胺Following step A in Example 14, 5-methoxy-2- (1-fluorenyl) · 4Η-3,1-benzohumone (100 mg, 0.33 mmol) and quinine were used Cyclo-3-amine (126 mg, 1.0 mmol) provided the title compound (55 mg, 39%). 1H NMR (400 MHz, CD3 OD) δ 1.86 (m, 1H), 2.01 (m, 2H), 2.24 (m, 1H), 2.30 (m, 1H), 3.18 (m, 1H), 3.31 (m , 4H), 3.72 (m, 1H), 3.94 (s, 3H), 4.40 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.53 (m, 1H), 7.56 (m, 4H), 7.79 (d, J = 6.8 Hz, 1H), 7.95 (m, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.34 (m, 1H); MS (ESI ) (M + H) +430.2. Example 92 N- (3-methoxy-2-{[(morpholine-3-ylmethyl) amino] carbonyl} phenyl) berberamine

於室溫下，將3-({[2-曱氧基-6-(1-莕甲醯基胺基）苯甲醯基] 胺基}甲基）嗎福啉-4·羧酸第三-丁酯（100毫克）在二氧陸圜中 101539 -107- 200539856 以4NHC1處理2小時。移除溶劑，提供標題化合物，為其HCl 鹽，定量產率。1H NMR (400 MHz，CD3 OD) 6 2.85 (m，2H)，3.42 (m， 1H)? 3.60 (m5 4H)5 3.75 (m, 1H), 3.95 (s5 3H), 3.98 (m, 1H)3 7.04 (dd5 J=8.05 1.2 Hz, 1H), 7.58 (m, 5H), 7.87 (dd, J=7.2, 1.2 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H)，8.06 (d，J=8.4 Hz，1H)，8_38 (d，J=8.0 Hz，1H); MS (ESI) (M+H)+420.2· 實例93 N-{3_甲氧基-2-[(嗎福啉斗基胺基）幾基]苯基}·ΐ_莕甲醯胺At room temperature, 3-({[2-fluorenyloxy-6- (1-fluorenylmethylamino) benzylamino] amino} methyl) morpholine-4 · carboxylic acid third -Butyl ester (100 mg) in dioxane 101539 -107- 200539856 treated with 4NHC1 for 2 hours. Removal of the solvent provided the title compound as its HCl salt in quantitative yield. 1H NMR (400 MHz, CD3 OD) 6 2.85 (m, 2H), 3.42 (m, 1H)? 3.60 (m5 4H) 5 3.75 (m, 1H), 3.95 (s5 3H), 3.98 (m, 1H) 3 7.04 (dd5 J = 8.05 1.2 Hz, 1H), 7.58 (m, 5H), 7.87 (dd, J = 7.2, 1.2 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8_38 (d, J = 8.0 Hz, 1H); MS (ESI) (M + H) + 420.2 · Example 93 N- {3_methoxy-2-[(morpholine bucket Amino group) phenyl group] phenyl}

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕基）-4H-3，1-苯并噚畊斗酮（100毫克，0.33毫莫耳）與嗎福啉_4_胺 (102毫克，1.0毫莫耳），提供標題化合物，為其TFA鹽（35毫 克，20%)。1HNMR(400MHz，CD3OD)5 2.87(m，4H)，3/73(m，4H)， 3.90 (s, 3H), 6.99 (d, J=8.4 Hz, 1H), 7.57 (m, 4H), 7.72 (m, 1H), 7.78 (d, J= 7·2 Hz，1H)，7·94 (d，J=8.4 Hz，1H)，8.02 (d，J=8.4 Hz，1H)，8.33 (d，J=8.0 Hz，1H) ; MS (ESI) (M+H)+406.2· 實例94 N-{3-曱氧基-2-[(六氫吡啶-1-基胺基）羰基]苯基}-l-莕甲醯胺Follow step A in Example 14 using 5-methoxy-2- (1-fluorenyl) -4H-3,1-benzopyrene ketone ketone (100 mg, 0.33 mmol) with Morpho Porphyrin-4 amine (102 mg, 1.0 mmol) provides the title compound as its TFA salt (35 mg, 20%). 1HNMR (400MHz, CD3OD) 5 2.87 (m, 4H), 3/73 (m, 4H), 3.90 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.57 (m, 4H), 7.72 (m, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H); MS (ESI) (M + H) + 406.2 · Example 94 N- {3-Methoxy-2-[(hexahydropyridin-1-ylamino) carbonyl] phenyl} -l-Metrazidine

101539 -108- 200539856 按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基）-4Η-3，1-苯并嘮畊_4_酮（100毫克，0.33毫莫耳）與六氫吡啶 小胺（100毫克，L0毫莫耳），提供標題化合物，為其TFA鹽 (24 毫克，14%)。1H NMR (400 MHz，CD3 OD) 5 1.56 (m，2H)，1·83 (m， 4H)，3.30 (m，4H)，3.92 (s，3H)，7·04 (d，J=8.4 Hz，1H)，7.56 (m，5H)，7·79 (d，J=6.0 Hz，1H)，7·95 (d, J=8.4 Hz，1H)，8·03 (d，J=8.4 Hz, 1H)，8·33 (d， 9·2 Hz，1H) ; MS (ESI) (M+H)+404.2. 實例95101539 -108- 200539856 According to the method in step A of Example 14 using 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1-benzopyrene-4_one (100 mg, 0.33 Mmol) and hexahydropyridine (100 mg, L0 mmol) provided the title compound as its TFA salt (24 mg, 14%). 1H NMR (400 MHz, CD3 OD) 5 1.56 (m, 2H), 1.83 (m, 4H), 3.30 (m, 4H), 3.92 (s, 3H), 7.04 (d, J = 8.4 Hz , 1H), 7.56 (m, 5H), 7.79 (d, J = 6.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.33 (d, 9.2 Hz, 1H); MS (ESI) (M + H) +404.2. Example 95

N-(2-{[(2-羥乙基）胺基]羰基}-3-甲氧苯基）小萘甲醯胺 〇/ 0 〇/ 0N- (2-{[(2-hydroxyethyl) amino] carbonyl} -3-methoxyphenyl) methylnaphthylamine 〇 / 0 〇 / 0

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕基)-4H-3，1-苯并口咢畊-4_酮（100毫克，〇·33毫莫耳）與2-胺基乙醇（61 毫克，1.0毫莫耳），提供標題化合物（72毫克，60%)。1H NMR (400 MHz, CDC13 ) δ 2.30 (m, 1H), 3.57 (m, 2H), 3.78 (m, 2H), 3.97 (s, 3H), 6.78 (d, J=8.4 Hz, 1H), 7.54 (m, 4H), 7.85 (m, 2H), 7.95 (d, J=8.2 Hz, 1H), 8.27 (s51H), 8.53 (d, J=8.0 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 12.55 (s, 1H)； MS (ESI) (M+H)+365.2. 實例96 N-(2-{[(2-羥丙基）胺基]羰基}-3-曱氧苯基)小莕甲醯胺 101539 -109- 200539856Following the procedure as in step A in Example 14, using 5-methoxy-2- (1-fluorenyl) -4H-3,1-benzopyrene-4_one (100 mg, 0.33 mmol) ) With 2-aminoethanol (61 mg, 1.0 mmol) to provide the title compound (72 mg, 60%). 1H NMR (400 MHz, CDC13) δ 2.30 (m, 1H), 3.57 (m, 2H), 3.78 (m, 2H), 3.97 (s, 3H), 6.78 (d, J = 8.4 Hz, 1H), 7.54 (m, 4H), 7.85 (m, 2H), 7.95 (d, J = 8.2 Hz, 1H), 8.27 (s51H), 8.53 (d, J = 8.0 Hz, 1H), 8.61 (d, J = 8.4 Hz , 1H), 12.55 (s, 1H); MS (ESI) (M + H) +365.2. Example 96 N- (2-{[(2-hydroxypropyl) amino] carbonyl} -3-fluorenoxybenzene Methyl) berberamine 101539 -109- 200539856

按照如實例14中步驟A之方法，使用5-甲氧基-2-〇莕 基）-4Η-3，1-苯并嘮啡-4-酮（100毫克，〇·33毫莫耳）與1-胺基丙-2-醇(75毫克，1.0毫莫耳），提供標題化合物（65毫克，52%)。 1H NMR (400 MHz, CDC13 ) 5 1.21 (d, J=6.4 Hz, 3H)5 2.34 (m, 1H), 3.27 (m，1H)，3.55 (m，1H)，3.96 (s，3H)，4.00 (m，1H)，6.78 (d，J=8.4 Hz，1H)， 7.54 (m, 4H), 7.86 (m, 2H), 7.95 (d, J=8.2 Hz, 1H), 8.21 (s, 1H), 8.53 (d, J= 8.0 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 12.49 (s, 1H) ； MS (ESI) (M+H)+379.2. 實例97 N-(2-{[(2-羥丁基）胺基]羰基}-3_曱氧苯基）-1-莕甲醯胺Following the procedure as in step A in Example 14, using 5-methoxy-2-oxo) -4'-3,1-benzofluoren-4-one (100 mg, 0.33 mmol) and 1-Aminopropan-2-ol (75 mg, 1.0 mmol) provided the title compound (65 mg, 52%). 1H NMR (400 MHz, CDC13) 5 1.21 (d, J = 6.4 Hz, 3H) 5 2.34 (m, 1H), 3.27 (m, 1H), 3.55 (m, 1H), 3.96 (s, 3H), 4.00 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 7.54 (m, 4H), 7.86 (m, 2H), 7.95 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H) , 8.53 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 12.49 (s, 1H); MS (ESI) (M + H) +379.2. Example 97 N- (2 -{[(2-hydroxybutyl) amino] carbonyl} -3_fluorenylphenyl) -1-carboxamidine

按照如實例14中步驟A之方法，使用5-甲氧基-2-(1-莕 基)-4Η-3，1-苯并哼畊-4-酮（100毫克，0.33毫莫耳）與丨_胺基丁冬 醇（89毫克，1·〇宅莫耳），提供標題化合物。MS (ESI) (Μ+Η)+ 393.2. 101539 -110-Following step A in Example 14 using 5-methoxy-2- (1-fluorenyl) -4fluorene-3,1-benzohumen-4-one (100 mg, 0.33 mmol) and Aminobutyrol (89 mg, 1.0 mol) provides the title compound. MS (ESI) (Μ + Η) + 393.2. 101539 -110-

Claims (1)

200539856 十、申請專利範圍： 非對映異構物、 1. 一種式I化合物或其藥學上可接受之鹽 對草異構物或混合物： 〇200539856 10. Scope of patent application: Diastereomers, 1. A compound of formula I or a pharmaceutically acceptable salt thereof. Isomers or mixtures: 〇 其中： m係選自〇, 1及2 ; η係選自〇，1，2,3,4及5 ; R1係獨立選自齒素、氰基、胺基、硝基、Ci6燒胺芙、 二^:卜6烷胺基、乙醯胺基、羥基、C1·6烷氧基、烷基、 鹵化4-6烷氧基、Ci-6烯基及鹵化q-6烷基； R2係選自C6-10芳基與(：2-10雜環基；其中該用於定義y 之1 0芳基與C：2· i 〇雜環基，係視情況被一或多個基團取 代，該基團係選自鹵素、函化(^_6烷基、C^6烷基、氛基、 石肖基、Cl _ 6烧氧基、函化Cl - 6烧氧基、經基、經基6烧 基、胺基、Ci-6烧氧基-Ci-6烧基、Ci _6烧魏基、（^·6燒氧罗炭 基、Cu烧胺基、二Ci-6烧基-胺基、胺基烧基、c3 6 環烷基、C2_6雜芳基、雜芳基-Ci — 6烷基、c6M0芳基及c6 10 芳基-Ci.6烷基；且 R3係選自氫與Ci-6烷基；R4係選自CV6烷基、c3 7環烧 基、c4_7環烯基、C6-10芳基、C2-6雜環基-胺基、c2-6雜環 基氧基-胺基及C2 - 6雜環基；其中該用於定義R4之6烧 101539 200539856 基、c3_7環烷基、（：4_7環烯基、c6-10芳基、c2_6雜環基-胺 基、c2_6雜環基氧基-胺基及c2-6雜環基，係視情況被一或 多個基團取代，該基團係選自鹵素、鹵化C1-6烷基、C16 烧基、氰基、硝基、Cle6烷氧基、鹵化Ci-6烷氧基、羥基、 經基-Ci-6烷基、胺基、Cl_6烷氧基-Cm烷基、心_6烷羰基、 Cl-6烧氧幾基、Cu烧胺基、二Ci-6烧基-胺基、胺基-Cm 烧基、CV6環烷基、c2_6雜芳基、雜芳基-Cl-6烷基、C6 l〇 知/CH2)「R4 芳基及CV10芳基-Ci·6烷基；或 R3 係為C2-10雜環 基’其係視情況被一或多個基團取代，該基團係選自鹵 素、經鹵素取代之。-6烷基、c1-6烷基、氰基、硝基、Ci 6 烧氧基、鹵化Q-6烷氧基、羥基、羥基_cl-6烷基、胺基、 Q-6烷氧基烷基、c1-6烷羰基、Ci 6烷氧羰基、Ci 6烷 胺基、二Ch烷基-胺基、胺基_Ci —烷基、（^乂環烷基、C26 雜芳基、雜芳基-Ch烷基、cv1()芳基及Q ι〇芳基_Ci # 基。 2.如請求項1之化合物，其中 m係選自〇, 1及2 ; η係選自〇, 1，2,3及4 ; 胺基、硝基、乙酿胺基、經 化Ci·3烷氧基及_化(^-3烷 R1係獨立選自_素、氰基、胺基 基、Cy烷氧基、Cl_3烷基、鹵化。 基；Wherein: m is selected from 0, 1 and 2; η is selected from 0, 1, 2, 3, 4 and 5; R1 is independently selected from halide, cyano, amine, nitro, Ci6 Di ^: 6 alkylamino, acetamido, hydroxyl, C1 · 6 alkoxy, alkyl, halogenated 4-6 alkoxy, Ci-6 alkenyl and halogenated q-6 alkyl; R2 is optional From C6-10 aryl and (: 2-10 heterocyclic group; where the 10 aryl group for y and C: 2 · i 〇 heterocyclic group are optionally substituted by one or more groups, This group is selected from the group consisting of halogen, halo (^-6 alkyl, C ^ 6 alkyl, aryl, schottyl, Cl-6 alkoxy, halo Cl-6 alkoxy, mesyl, and oxo 6) Group, amine group, Ci-6 alkyloxy-Ci-6 alkyl group, Ci-6 alkyl group, (6-6 alkyloxy carbon group, Cu alkyl group, di Ci-6 alkyl group-amine group, amine Alkyl, c3 6 cycloalkyl, C2-6 heteroaryl, heteroaryl-Ci-6 alkyl, c6M0 aryl, and c6 10 aryl-Ci.6 alkyl; and R3 is selected from hydrogen and Ci-6 Alkyl; R4 is selected from CV6 alkyl, c3 7 cycloalkenyl, c4_7 cycloalkenyl, C6-10 aryl, C2-6 heterocyclyl-amino, c2-6 heterocyclyloxy-amine, and C2-6 heterocyclyl; where this is used to define R4-6 101539 200539856 group, c3_7 cycloalkyl group, (: 4_7 cycloalkenyl group, c6-10 aryl group, c2_6 heterocyclyl-amino group, c2_6 heterocyclyloxy-amino group, and c2-6 heterocyclic group, depending on the situation Substituted by one or more groups selected from the group consisting of halogen, C1-6 alkyl halide, C16 alkyl, cyano, nitro, Cle6 alkoxy, halogen Ci-6 alkoxy, hydroxyl, -Ci-6 alkyl, amine, Cl-6 alkoxy-Cm alkyl, hexa-6 alkylcarbonyl, Cl-6 oxoyl, Cu amine, di Ci-6 alkoxy-amine, amine -Cm alkyl, CV6 cycloalkyl, c2-6 heteroaryl, heteroaryl-Cl-6 alkyl, C6 l0 / CH2) "R4 aryl and CV10 aryl-Ci · 6 alkyl; or R3 Is a C2-10 heterocyclyl group, which is optionally substituted by one or more groups, the group is selected from halogen, halogen substituted.-6 alkyl, c1-6 alkyl, cyano, nitrate Group, Ci 6 alkoxy group, halogenated Q-6 alkoxy group, hydroxyl group, hydroxy_cl-6 alkyl group, amino group, Q-6 alkoxyalkyl group, c1-6 alkylcarbonyl group, Ci 6 alkoxycarbonyl group, Ci 6 alkylamino, diChalkyl-amino, amine_Ci-alkyl, (^ cycloalkyl, C26 heteroaryl, heteroaryl-Chalkyl, cv1 () aryl And Q ι〇aryl_Ci # group. 2. The compound according to claim 1, wherein m is selected from the group consisting of 0, 1 and 2; η is selected from the group consisting of 0, 1, 2, 3 and 4; , Ethyl alcohol, Ci · 3 alkoxy group, and ^ -3 alkane R1 are independently selected from the group consisting of halogen, cyano, amino, Cy alkoxy, Cl_3 alkyl, and halogenation. base; 101539 200539856 代，該基團係選自鹵素、鹵化(^_3烷基、C^-3烷基、硝基、 Q-3烷氧基、鹵化Cu烷氧基、羥基、羥基-Cw烷基、胺 基、Ci-3烷氧基-Cu烷基、C2_5雜環基-Cu烷基、Ci-6烷氧 罗炭基、Ci- 3烧胺基、二Ci- 3烧基β胺基及胺基- 3炫基，且 R3係選自氫與CV6烷基；R4係選自（^-6烷基、C3-7環烷 基、C2_6雜環基-胺基、C2_6雜環基氧基·胺基及C2-6雜環 基；其中該用於定義R4之(^-6烷基、C3_7環烷基、（：2_6雜環 基-胺基、C2_6雜環基氧基_胺基及C2_6雜環基，係視情況被 一或多個基團取代，該基團係選自南素、齒化Ci-3烷基、 Ci-3烷基、硝基、（^-3烷氧基、函化心」烷氧基、羥基、羥 基-Ci-3烷基、胺基、Ci-3烷氧基-Ci-3烷基、Cbe烷氧羰基、 Cu烷胺基、二Ci-3烷基-胺基及胺基-Ch烷基；或 知多H2)n—R4 r3 係選自一氮七圜烷基、吡咯基、二氫吡咯基、 四氫卩比u各基、u米嗤基、四氫u米嗤基、峨嗤基、二氫卩比嗤基、 四氫卩比唆基、異四氫p号嗤基、三嗤基、嗎福淋基、六氫叶匕 σ定基、硫代嗎福淋基、塔p井基、六氫说u井基、三〃井基或1，4-二氧-8-氮螺[4·5]癸-8-基；其中該一氮七圜烷基、吡咯基、 二氫吡咯基、四氫吡洛基、咪唑基、四氫咪唑基、卩比唑基、 二氫卩比嗅基、四氫卩比峻基、異四氫崎唾基、三嗤基、嗎福 啉基、六氫吡啶基、硫代嗎福啉基、六氫吡啡基、三啩基 及1，4-二氧-8-氮螺[4.5]癸-8-基，係視情況被一或多個基團取 代，該基團係選自鹵素、鹵化q-3烷基、q-3烷基、硝基、 (^-3烷氧基、鹵化A」烷氧基、羥基、羥基-Cy烷基、胺 101539 200539856 基、Cl-3烷氧基-Ci-3烷基、C^-6烷氧羰基、（^_3烷胺基、二 Cl · 3烧基-胺基及胺基-Ci - 3烧基。 3.如請求項1之化合物，其中 m係選自〇與1 ; η係選自〇, 1，2, 3及4 ; R1係獨立選自鹵素、胺基、硝基、乙醯胺基、經基、 ci_3烷氧基、Ci-3烷基、齒化(^-3烷氧基及鹵化C^-3烷基； R2係選自苯基、莕基、吡啶基、吡畊基、嘧啶基、嗒啡 基、4吩基、呋喃基、吡咯基、咪唑基、嘍唑基、噚唑基、 口比嗤基、異嘧唑基、異嘮唑基、1，2,3_三唑基、四唑基、ι，2,3-嘍二唑基、1，2,3_$二唑基、1，2,4_三唑基、1，2,4-遠二唑基、 I2,4』号二唑基、1，3,4_三唑基、1，3,4-嘧二唑基及1，3,4嘮二唑 基㈤p木基、二氮丨嗓基、峻琳基、四氮u奎淋基、異p奎p林 基、四氫異喹啉基、1，4_苯并二氧陸圜基、香豆素、二氩 香豆基、2,3-二氫苯并呋喃基、ι，2-苯并異呤唑基、13-苯并 二氧伍圜烯基、2,3-二氫·1，4-苯并二氧陸圜烯基、3,4-二氫 々Η-1，5·笨并二氧氮七圜烯基、4Η-1，3-苯并二氧陸圜烯基、 苯并呋喃基、苯并硫苯基、苯并哼唑基、苯并嘧唑基、苯 并味嗤基、笨并三嗤基、硫基黃嘌吟基、吟嗤基、叶淋基、 外唆基、峨咯里西啶基及喳諾里西啶基，其係視情況被一 或多個基團取代，該基團係選自齒素、羥基、甲基、甲氧 基、胺基、三氟曱基、三氟曱氧基、甲氧基甲基、1Η-1，2,3_ 三嗤基甲基及1Η_吡唑基曱基； R3係選自氫與Cl-6烷基；且 101539 200539856101539 200539856 generation, the group is selected from halogen, halogenated (^ _3 alkyl, C ^ -3 alkyl, nitro, Q-3 alkoxy, halogenated Cu alkoxy, hydroxyl, hydroxy-Cw alkyl, Amine group, Ci-3 alkoxy-Cu alkyl group, C2_5 heterocyclyl-Cu alkyl group, Ci-6 alkoxycarbyl group, Ci-3 alkylamino group, di Ci-3 alkylamino group and amine -3, and R3 is selected from hydrogen and CV6 alkyl; R4 is selected from (^ -6 alkyl, C3-7 cycloalkyl, C2-6 heterocyclyl-amine, C2-6 heterocyclyloxy · Amine group and C2-6 heterocyclic group; where this is used to define (4-6 alkyl group, C3_7 cycloalkyl group, (: 2-6 heterocyclyl-amino group, C2_6 heterocyclyloxy_amino group and C2_6 Heterocyclyl, which is optionally substituted by one or more groups, the group is selected from the group consisting of Nansu, Ci-3 alkyl, Ci-3 alkyl, nitro, (^ -3 alkoxy, `` Hanhuaxin '' alkoxy, hydroxy, hydroxy-Ci-3 alkyl, amine, Ci-3 alkoxy-Ci-3 alkyl, Cbe alkoxycarbonyl, Cu alkylamino, di Ci-3 alkyl -Amino and amine-Chalkyl; or H2) n-R4 r3 is selected from monoazaheptyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolidyl, Tetrahydro u meter Fluorenyl, erbyl, dihydropyridyl, tetrahydropyridyl, isotetrahydrop-methyl, trimethyl, morpholin, hexahydropyridine, thiomorpholin Base, tower p-well base, hexahydro-ortho-well base, stilbene well-base, or 1,4-dioxo-8-azaspiro [4 · 5] dec-8-yl; Pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, imidazolyl, tetrahydroimidazolyl, hydrazolyl, dihydropyrrolyl, tetrahydropyrrolyl, isotetrahydrozalyl, stilbene Group, morpholinyl, hexahydropyridyl, thiomorpholinyl, hexahydropyridinyl, trifluorenyl and 1,4-dioxo-8-azaspiro [4.5] dec-8-yl, system Optionally substituted by one or more groups selected from halogen, halogenated q-3 alkyl, q-3 alkyl, nitro, (^ -3 alkoxy, halogenated A "alkoxy, Hydroxyl, hydroxy-Cy alkyl, amine 101539 200539856, Cl-3 alkoxy-Ci-3 alkyl, C ^ -6 alkoxycarbonyl, (^ _3 alkylamino, di-Ci-3 alkyl-amino And amine-Ci-3. 3. The compound according to claim 1, wherein m is selected from 0 and 1; η is selected from 0, 1, 2, 3 and 4; R1 is independently selected from halogen , Amino, nitro, acetamido, mesityl, ci_3 alkoxy, Ci-3 alkyl, dentified (^ -3 alkoxy and halogenated C ^ -3 alkyl; R2 is selected from phenyl , Fluorenyl, pyridyl, pyrimidinyl, pyrimidinyl, daphnyl, 4-phenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, oxazolyl, oxazolyl, isopyrimidyl, isopropyl Oxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-oxadiazolyl, 1,2,3_ $ diazolyl, 1,2,4-triazolyl, 1 , 2,4-Dioxadiazolyl, I2,4 "diazolyl, 1,3,4-triazolyl, 1,3,4-pyrimadiazole and 1,3,4 oxadiazolyl p Wood-based, diazepine, junyl, tetrazine, quinolinyl, isopropylquinyl, tetrahydroisoquinolinyl, 1,4-benzodioxolyl, coumarin, Diargoncoumanyl, 2,3-dihydrobenzofuranyl, ι, 2-benzoisoxazolyl, 13-benzodioxolenyl, 2,3-dihydro · 1,4- Benzodioxolenyl, 3,4-dihydrofluorene-1,5 · benzodioxazepinenyl, 4fluorene-1,3-benzodioxolhenyl, benzofuran Base, benzothiophenyl, benzohumazolyl, benzopyrazolyl, benzo misoyl, benzylidene Trisyl, thioxanthyl, cynoyl, phyllyl, exoyl, erolizidinyl, and panoroxinyl, which are optionally substituted by one or more groups, The group is selected from the group consisting of halide, hydroxy, methyl, methoxy, amine, trifluorofluorenyl, trifluorofluorenyloxy, methoxymethyl, 1′-1,2,3_trifluorenylmethyl And 1′-pyrazolylfluorenyl; R3 is selected from hydrogen and Cl-6 alkyl; and 101539 200539856 」一胺基、六氫吡啶-1-胺基、〇-環己基羥胺基、〇- 四氫卩比各一'' Monoamine, hexahydropyridine-1-amino, 0-cyclohexylhydroxylamino, 0-tetrahydropyrene each ^戍基m胺基、0-環丁基羥胺基、〇-環丙基羥胺基及Cu 炫基，其係視情況被一或多個基團取代’該基團係選自鹵 素、胺基、胺基曱基、2-胺基乙基、羥基、羥基曱基、甲 基及乙基。 4.如請求項3之化合物，其中 R2係選自^ Amino group, amino group, 0-cyclobutylhydroxylamino group, 0-cyclopropylhydroxylamino group, and Cuxyl group, which are optionally substituted by one or more groups. The group is selected from halogen, amino group , Aminoamido, 2-aminoethyl, hydroxy, hydroxyamido, methyl, and ethyl. 4. The compound of claim 3, wherein R2 is selected from 101539 200539856101539 200539856 其係視情況被 '一或夕個基團取代’該基團係選自鹵 素、曱基、甲氧基、羥基、甲氧基甲基、1H-1，2,3-三唑基甲 基及1H-1，2-二唑基甲基。 5·如請求項1之化合物，其中m為1 ; η係選自〇, 1，2及3 ; R1係獨立選自_素、胺基、硝基、乙醯胺基、經基、 Ci-3院氧基、Ci-3烧基、齒化Cl-3烧氧基及齒化Ci-3烧基； R2係選自苯基、莕基、# b唆基、被1^井基、痛咬基、塔〃井 基、p塞吩基、吱鳴基、峨洛基、味11坐基、P塞嗤基、吟。坐基、 吡唑基、異嘧唑基、異噚唑基、1，2,3-三唑基、四唑基、1，2,3-嘍二唑基、1，2,3-噚二唑基、1，2,4-三唑基、1，2,4-嘧二唑基、 1，2,4_今二唑基、1，3,4-三唑基、1，3,4-魂二唑基及1，3,4-嘮二嗤 101539 200539856It is optionally substituted by 'one or more groups' This group is selected from halogen, amidino, methoxy, hydroxyl, methoxymethyl, 1H-1,2,3-triazolylmethyl And 1H-1,2-diazolylmethyl. 5. The compound according to claim 1, wherein m is 1; η is selected from the group consisting of 0, 1, 2, and 3; R1 is independently selected from the group consisting of molybdenum, amino, nitro, acetamido, meridian, Ci- 3-Hydroxy, Ci-3Hydroxy, D3H-Cl-3Hydoxy, and D3H-Ci-3H2; R2 is selected from the group consisting of phenyl, fluorenyl, #b fluorenyl, hydrazone, and Bite base, Tarim base, p-secenyl, squeaky base, erogen, Wei 11 base, P-seth base, Yin. Sorryl, pyrazolyl, isopyrazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazine Oxazolyl, 1,2,4-triazolyl, 1,2,4-pyrimidazolyl, 1,2,4-diamidazolyl, 1,3,4-triazolyl, 1,3,4 -Oxadiazolyl and 1,3,4-fluorene difluorene 101539 200539856 基、⑼哚基、二氫吲哚基、喳啉基、四氫喹啉基、異喳啉 基、四氫異喹啉基、1，4-苯并二氧陸圜基、香豆素、二氫 香豆基、2,3-二氫苯并呋喃基、丨，2-苯并異呤唑基、u_苯并 二氧伍圜烯基、2,3-二氫-1，4·苯并二氧陸圜烯基、3,4-二氫 -2Η-1，5-本并一氧亂七圜稀基、4Η_1，3-苯并二氧陸圜稀基、 苯并吱喃基、苯并硫苯基、苯并吟ϋ坐基、苯并ρ塞嗤基、苯 并σ米嗤基、苯并三嗤基、硫基黃嗓吟基、叶β坐基、叶琳基、 吖啶基、吡咯里西啶基及喹諾里西啶基，其係視情況被一 或多個基團取代，該基團係選自函素、羥基、甲基、甲氧 基、胺基、三氟甲基、三氟曱氧基、甲氧基甲基、1Η-1，2,3_ 且 唑基甲基、1Η-吡唑基曱基； '(CH2)n-R4 R3 係選自一氮四圜基、一氮七圜烷基、異四 氫哼唑基、嗎福啉基、六氫吡畊基、六氫吡啶基、四氫吡 咯基及1，4-二氧-8-氮螺[4.5]癸-8-基，其係視情況被一或多個 基團取代，該基團係選自鹵素、氰基、硝基、曱基、乙基、 羥基、羥基-甲基、羥基-乙基、胺基-甲基、胺基-乙基、甲 氧基-甲基、甲氧基-苯基、乙氧羰基、第三-丁氧羰基、二 苯基-甲基、嗎福啉基-乙-2-基、六氫吡啶基-甲基及吡啶基 K ,(CH2)-R4 係選自 如請求項之5化合物 101539 -7- 200539856Group, fluorinyl, dihydroindolyl, fluorinyl, tetrahydroquinolyl, isofluorinyl, tetrahydroisoquinolyl, 1,4-benzodioxolyl, coumarin, Dihydrocoumaryl, 2,3-dihydrobenzofuranyl, 1,2, benzobenzoxazinyl, u-benzodioxolenyl, 2,3-dihydro-1,4 · Benzodioxolanyl, 3,4-dihydro-2fluorene-1,5-benzodioxane heptadiene, 4Η_1,3-benzodioxolidine, benzocranyl , Benzothiophenyl, benzoindanyl, benzoρethenyl, benzoσmethylbenzyl, benzotrisinyl, thioxanthenyl, leaf β sitting group, yelinyl, acridine Group, pyrrolizidinyl group and quinolosidinyl group, which are optionally substituted by one or more groups, the group is selected from the group consisting of functional groups, hydroxyl groups, methyl groups, methoxy groups, amine groups, Fluoromethyl, trifluorofluorenyloxy, methoxymethyl, 1′-1,2,3_ and azolylmethyl, 1′-pyrazolylfluorenyl; '(CH2) n-R4 R3 is selected from mononitrogen Tetrafluorenyl, monoazaheptyl, isotetrahydrohumidyl, morpholinyl, hexahydropyridyl, hexahydropyridyl, tetrahydropyrrolyl, and 1,4-dioxo-8-nitrogen Spiro [4.5] dec-8-yl, which is optionally substituted with one or more groups selected from halogen, cyano, nitro, fluorenyl, ethyl, hydroxy, hydroxy-methyl, Hydroxy-ethyl, amino-methyl, amino-ethyl, methoxy-methyl, methoxy-phenyl, ethoxycarbonyl, tert-butoxycarbonyl, diphenyl-methyl, Fluorolinyl-ethyl-2-yl, hexahydropyridyl-methyl and pyridyl K, (CH2) -R4 is selected from 5 compounds as claimed in claim 101539 -7- 200539856 7.如請求項5或6之化合物，R2係選自 101539 2005398567. If the compound of claim 5 or 6, R2 is selected from 101539 200539856 其係視情況被一或多個基團取代’該基團係選自鹵 素、甲基、曱氧基、羥基、甲氧基甲基、1H-l，2,3-三唑基甲 基及比嗤基甲基。 8·如請求項1-6中任一項之化合物，其中 R2係選自It is optionally substituted by one or more groups. The group is selected from the group consisting of halogen, methyl, methoxy, hydroxy, methoxymethyl, 1H-1,2,3-triazolylmethyl, and More than methyl. 8. The compound according to any one of claims 1-6, wherein R2 is selected from 素 ，其 、甲 101539 200539856 基、甲氧基、羥基、甲氧基甲基、1H-1，2,3-三唑基甲基及1H- 吡唑基甲基。 9. 一種化合物，其係選自： N-[4-氣基-2-[[[(l-乙基-2-四氫吡咯基）甲基]胺基]羰基]苯 基]-1-莕羧醯胺； N-[4-氣基-2-[[[2-(4-嗎福啉基）乙基]胺基]羰基]苯基；莕羧 醯胺； Ν-[4-氣基-2-[[4-[2-(4-嗎福琳基）乙基]-1-六氫π比〃井基]魏基] 苯基]小莕羧醯胺； Ν-[4-氣基-2-[[[2-(二甲胺基）乙基]胺基]羰基]苯基]小莕羧 醯胺； Ν-[4-氣基-2-[(4-嗎福琳基胺基）幾基]苯基]-1-茶叛酿胺； Ν-[4-氣基-2-[(4-乙基-1-六氳吡畊基）羰基]苯基]-1-莕羧醯 胺； Ν-[4-氣基-2-[[[3-(4-嗎福淋基）丙基]胺基]幾基]苯基]-1-莕叛 醯胺； Ν-[4-氣基-2-[[(4-六氫吡啶基曱基）胺基]羰基]苯基]-1_萘羧 醯胺； Ν-[2-[[4-(胺基甲基>1-六氫吡啶基]羰基]-4-氣苯基]-1_莕羧 醯胺； Ν-[2-[[4-(2-胺基乙基）-1-六氫吡畊基]羰基]-4-氯苯基]-1-莕 羧醯胺； N-[4-氣基-2-[[[2-(l-六氫吡畊基）乙基]胺基]羰基]苯基]-1·莕 羧醯胺； 101539 • 10- 200539856 N-[4-(乙醯胺基）-2-[[(環己基甲基）胺基機基]苯基Η-萘羧 醯胺； Ν-[4-胺基冬[[(環己基甲基）胺基]羰基]苯基]小莕羧醯胺； Ν-[4-氣基-2_[[[(四氫_2Η-哌喃_4_基）曱基]胺基]羰基]苯 基]-1-莕羧醯胺； Ν-[4-氣基-2-[[(環丙基甲基）胺基]羰基]苯基]-1·莕羧醯胺； Ν-[4-氣基-2-[(環己胺基）羰基]苯基]-1·莕羧醯胺； Ν-[4-氣基-2-[[(環丁基曱基）胺基]羰基]苯基]小莕羧醯胺； Ν-[4-氣基_2-[[(環庚基甲基)胺基]羰基]苯基]-1-莕羧醯胺； Ν·[4-氣基-2-[[[(2-羥基環己基）甲基]胺基]羰基]苯基]-1-莕 羧醯胺； Ν-[4-氣基-2-[(3-羥基-1-六氫吡啶基）羰基]苯基Η-莕羧醯 胺； Ν-[4-氣基-2-[[3-(羥甲基）小六氫吡啶基]羰基]苯基>1-莕羧 醯胺； Ν-[4-氯基-2-[(六氫-1Η-—氮七圜烯-1-基）羰基]苯基]-1-莕羧 酿胺； Ν-[4-氣基-2-(1_四氫峨洛基魏基）苯基]-1-莕叛酿胺； Ν-[4-氣基-2-[[(2-經基環己基）胺基]幾基]苯基]-1_審敌酿 胺； Ν-[4-氣基·2-[[[2-(1，3_二氧伍圜-2-基）乙基]胺基]羰基]苯 基]-1-審羧醯胺； Ν-[4-氯基-2-[[[1-(經甲基）環戊基]胺基]幾基]苯基]_1_莕緩 醯胺； 101539 -11- 200539856 N-[4-氣基-2-[(3-經基-1-四氫p比洛基）幾基]苯基]-1-茶致醯 胺； N-[4-氯基-2-[[2-(2-甲氧苯基）小四氫吡咯基]羰基]苯基]·μ 萘羧醯胺； Ν-[4-氣基-2-[[(1，3-二氧伍圜-2-基甲基）胺基]羰基]苯基]-1- 莕羧醯胺； Ν-[4-氯基-2-[[(四氫-2Η-哌喃-4-基）胺基]羰基]苯基]-1-萘羧 醯胺； Ν-[4-氯基-2-[[[2-(四氫-2Η-哌喃-4-基）乙基]胺基]羰基]苯 基]小莕羧醯胺； Ν-[4-氣基-2-[[(1，3_二氧伍圜-2-基甲基）甲胺基]羰基]苯 基]-1-莕羧醯胺； Ν-[4-氣基-2-[[2-(2-吡啶基>1-四氫吡咯基]羰基]苯基]-1-莕 羧醯胺； Ν-[4-氣基-2-[[2-(1-六氫吡啶基甲基>1-六氫吡啶基]羰基] 苯基]-1-莕羧醯胺； Ν-[2-[[(環己基甲基）胺基Μ基]_4_甲基苯基]-卜萘羧醯胺； Ν-[2-[[(環丁基甲基）胺基课基Η-甲基苯基]-1-莕羧醢胺； Ν-[2-[[(環己基甲基）胺基]羰基]-4-氟苯基]-1-莕羧醯胺； Ν-[2-[[(環丁基甲基）胺基]羰基]-4·氟苯基]-1-莕羧醯胺； Ν-[2-[[(環己基甲基)胺基Μ基]-6-甲氧苯基]-1-莕羧醯胺； Ν-[2-氣基各[[(環己基曱基）胺基]羰基]苯基]-1-蓁羧醯胺； Ν-[2-[[(環己基曱基)胺基]Μ基]-6_甲基苯基]小莕羧醯胺； Ν-[5-氣基-2-[[(環己基甲基)胺基]羰基]苯基]_1_莕羧醯胺； 101539 -12- 200539856 N-[3-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-1-莕羧醯胺； Ν-[3-氣基-2-[[(環丁基甲基）胺基]羰基]苯基Η·莕羧醯胺； Ν-[2-[[(環己基甲基）胺基]幾基]-3-甲基苯基]-1-莕羧醯胺； Ν-[2-[[(環己基甲基）胺基]幾基]-4,5-二甲氧基苯基]茶緩 醯胺； Ν-[2-[[(環己基甲基）胺基]幾基]-3-甲氧苯基]-1_莕羧醯胺； Ν_[2-[[(環丁基甲基）胺基]幾基]-3_甲氧苯基]-1-莕羧醯胺； Ν-[2-[[(環己基甲基）胺基]羰基]-3-羥苯基]-l-莕羧醯胺； Ν-[2-[[(環丁基甲基）胺基]幾基]-3-經苯基]小莕羧醯胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-8-喳啉羧醯 胺； Ν-[4-氣基-2_[[(環己基甲基）胺基]羰基]苯基]_2_喹啉羧醯 胺； Ν-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-2-喹呤啉緩 醯胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-1-莕羧醯胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-3-喳啉羧醯 胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-吡畊羧醯 胺； Ν-[4-氯基-2-[[(環己基曱基）胺基]羰基]苯基]-3-嗒畊羧醯 胺； Ν-[4-氯基-2-[[(環己基甲基)胺基]羰基]苯基]-2-茶羧醯胺； Ν-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-4-吡啶羧醯 101539 •13- 200539856 胺； N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]_3_吡啶羧醯 胺； 2-(苯甲醯胺基）_5•氣(環己基甲基）_苯甲醯胺； N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-3,4-二氫 -2H-1，5-苯并二氧氮七圜烯-7-羧醯胺； N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,3·二氫_7-苯 并呋喃羧醯胺； Ν-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-1-異喹啉羧 醯胺； Ν-[4-氣基-2-[[(環己基曱基）胺基]羰基]苯基]-4-喳啉羧醯 胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-4-唓啉羧醯 胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-甲氧基-1-莕 羧醯胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-吡啶羧醯 胺； Ν-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-氟基-3-(三 氟曱基）-苯甲醯胺； N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,3-二氟-苯甲 醯胺； 3_氯-N-[4_氯基-2_[[(環己基甲基）胺基]幾基]苯基]_2_氟-笨 曱醯胺； 101539 -14- 200539856 N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,3-二甲基-苯 甲醯胺； N-[4-氯基-2-[[(環己基甲基）胺基]羰基]苯基]-3-氟基-2-(三 氟甲基）-苯甲醯胺； N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,2-二氟-1,3-苯并二氧伍圜烯-4-羧醯胺； N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-6-氟基-4H-1，3- 苯并二氧陸圜烯-8-羧醯胺； N-[4-氣基冬[[(環己基甲基）胺基]羰基]苯基]-2-曱基-3-(三 氟曱基）-苯甲醯胺； 3-氣-N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2-甲基- 笨曱醯胺； N-[4-氣基-2-[[(環己基甲基）胺基]羰基]苯基]-2,3-二甲氧基- 苯曱醯胺； N-[4-氣基-2-[[(環己基曱基)胺基]羰基]苯基]-3_甲氧基-2-曱 基-苯甲醯胺； Ν-[4·氣基_2_[[(環己基曱基）胺基]羰基]苯基]-5-異喹啉羧 醯胺； 6-氣-Ν-[4-氣基_2-[[(環己基甲基)胺基Μ基]苯基]-2-氟基-3- 甲基-苯甲醯胺； 2-氣-Ν-[4-氣基-2-[[(環己基曱基）胺基]魏基]苯基]-3-(三氟 曱基）-苯曱醯胺； N-[4-氣基·2-[[(環己基曱基）胺基]羰基]笨基]-5-喳啉羧醯 胺； 101539 •15- 200539856 N-[2-[[(環己基甲基）胺基機基]_4-甲氧苯基η•萘羧醯胺； Ν_(3-甲氧基_2-{[(2-六氫吡啶-1_基乙基）胺基]羰基}苯基）+ 萘曱酸胺； Ν_(2-{[(1，4-二氧陸圜-2-基曱基）胺基]幾基}-3-甲氧苯基）-1_ 莕曱醯胺； N-(3-曱氧基_2_{[(2-嗎福啉-4-基乙基）胺基]羰基}苯基)小莕 曱醯胺； N-(3-甲氧基冬{[(2-四氫吡咯-1-基乙基）胺基]羰基}苯基）-i- 茶曱醯胺； N-{3-甲氧基-2_[(四氫-2H-哌喃-4-基胺基）羰基]苯基卜1-莕 曱醯胺； 3-({[2-曱氧基-6-(1_莕甲醯基胺基）苯甲醯基]胺基}甲基）嗎 福啉-4-羧酸第三-丁酯； Ν-{2-[(1-氮雙環并[2.2.2]辛-3-基胺基）羰基]_3_曱氧苯基}·1- 萘曱醯胺； Ν-(3-甲氧基-2-{[(嗎福啉-3-基甲基）胺基]羰基}苯基）小莕 曱醯胺； Ν-{3-甲氧基·2_[(嗎福啉-4-基胺基）羰基]苯基}小莕曱醯 胺； Ν-{3-甲氧基-2-[(六氫吡啶-1-基胺基）羰基]苯基}小莕曱醯 胺； Ν-(2-{[(2-羥乙基）胺基]羰基}-3-甲氧苯基）小莕甲醯胺； Ν-(2-{[(2-羥丙基）胺基]羰基}-3-曱氧苯基）-1-莕甲醯胺； N-(2-{[(2_羥丁基）胺基博基}_3_甲氧苯基)-1_莕甲醯胺； 101539 -16- 200539856 及其藥學上可接受之鹽。 10.如請求項1 & 、力、9中任一項之化合物，其係作為藥劑使用。 種女明求項丨-9中任一項之化合物於藥劑製造上之用 途，該藥劑係用於治療疼痛。 12·種如5月求項1-9中任一項之化合物於藥劑製造上之用 途，該藥劑係用於治療功能性胃腸病症。Element, its methyl group, 101539 200539856 group, methoxy group, hydroxy group, methoxymethyl group, 1H-1,2,3-triazolylmethyl group and 1H-pyrazolylmethyl group. 9. A compound selected from the group consisting of: N- [4-airyl-2-[[[((l-ethyl-2-tetrahydropyrrolyl) methyl] amino] carbonyl] phenyl] -1- Fluorocarboxamide; N- [4-Gamo-2-[[[[2- (4-morpholinyl) ethyl] amino] carbonyl] phenyl; phenylcarboxamide; NH- [4-Ga Phenyl-2-[[4- [2- (4-morpholinyl) ethyl] -1-hexahydroπ than hydrazone] weiyl] phenyl] berberylcarboxamide; Ν- [4- Carbo-2-[[[2- (dimethylamino) ethyl] amino] carbonyl] phenyl] berberylcarboxamide; N- [4-Gamo-2-[(4-morpholin Amino group) several groups] phenyl] -1-Tetramethylamine; N- [4-airyl-2-[(4-ethyl-1-hexapyridyl) carbonyl] phenyl] -1 -Fluorenylcarboxamide; Ν- [4-airyl-2-[[[[3- (4-morpholinyl) propyl] amino] amido] phenyl] -1-carbamidine; Ν -[4-Amino-2-[[(4-hexahydropyridylfluorenyl) amino] carbonyl] phenyl] -1-naphthylcarboxamide; Ν- [2-[[4- (aminomethyl ≫ 1-hexahydropyridyl] carbonyl] -4-aminophenyl] -1-carboxamidine; N- [2-[[4- (2-aminoethyl) -1-hexahydropyridine Aryl] carbonyl] -4-chlorophenyl] -1-carboxamidine; N- [4-airyl-2-[[[2- (l-hexahydropyridyl) ethyl] amino] Carbonyl] phenyl] -1 · carboxamidine ; 101539 • 10- 200539856 N- [4- (ethylamido) -2-[[(cyclohexylmethyl) amino] phenylphenyl-naphthylcarboxamide; N- [4-amino [[(Cyclohexylmethyl) amino] carbonyl] phenyl] berberylcarboxamide; Ν- [4- 气 基 -2 _ [[((Tetrahydro_2Η-piperan_4_yl) fluorenyl] Amine] carbonyl] phenyl] -1-carboxamidine; N- [4-airyl-2-[[(cyclopropylmethyl) amino] carbonyl] phenyl] -1 · carboxamidine ; Ν- [4-amino-2-[(cyclohexylamino) carbonyl] phenyl] -1 · fluorenylcarboxamide; NR- [4-airyl-2-[[(cyclobutylfluorenyl) Amine] carbonyl] phenyl] besylcarboxamidine; N- [4-airyl_2-[[(cycloheptylmethyl) amino] carbonyl] phenyl] -1-carboxamidine; Ν · [4-Gas-2--2-[[[(2-hydroxycyclohexyl) methyl] amino] carbonyl] phenyl] -1-carboxamidine; Ν- [4-Gas-2-[( 3-hydroxy-1-hexahydropyridyl) carbonyl] phenylfluorene-fluorenecarboxamidine; N- [4-airyl-2-[[3- (hydroxymethyl) small hexahydropyridyl] carbonyl] benzene ≫1-fluorenylcarboxamide; N- [4-chloro-2--2-((hexahydro-1fluoren-azaazene-1-enyl) carbonyl] phenyl] -1-carboxamide; Ν- [4-Amino-2- (1-tetrahydroerlocylweiyl) phenyl] -1-pyreneamine; Ν -[4-Amino-2-[[(2-Cyclocyclohexyl) amino] Jiyl] phenyl] -1_diamine amine; Ν- [4- 气 基 · 2-[[[2 -(1,3-dioxofluoren-2-yl) ethyl] amino] carbonyl] phenyl] -1-carboxamidine; N- [4-chloro-2-[[[1- ( Via methyl) cyclopentyl] amino] several phenyl] phenyl] _1_sulfonylamine; 101539 -11- 200539856 N- [4-airyl-2-[(3-meryl-1-tetrahydro pBiloxyl) Isyl] phenyl] -1-theramine; N- [4-chloroyl-2-[[2- (2-methoxyphenyl) small tetrahydropyrrolyl] carbonyl] benzene []] Naphthylcarboxamide; N- [4-airyl-2-[[(1,3-dioxol-2-ylmethyl) amino] carbonyl] phenyl] -1-fluorenylcarboxyl Amidoamine; Ν- [4-chloro-2--2-[[(tetrahydro-2Η-piperan-4-yl) amino] carbonyl] phenyl] -1-naphthylcarboxamide; Ν- [4-chloro Yl-2-[[[2- (tetrahydro-2Η-piperan-4-yl) ethyl] amino] carbonyl] phenyl] berberylcarboxamide; Ν- [4- 气 基 -2- [ [(1,3-Dioxo-2-ylmethyl) methylamino] carbonyl] phenyl] -1-fluorenecarboxamide; Ν- [4- 气 基 -2-[[2- (2 -Pyridyl > 1-tetrahydropyrrolyl] carbonyl] phenyl] -1-fluorenylcarboxamide; N- [4-airyl-2-[[2- (1-hexahydropyridylmethyl) > 1-hexahydropyridyl] carbonyl] benzene ] -1-fluorenecarboxamide; Ν- [2-[[(cyclohexylmethyl) aminomethyl]]-4-methylphenyl] -naphthylcarboxamide; Ν- [2-[[(cyclo Butylmethyl) aminobenzyl-methylphenyl] -1-fluorenecarboxamide; N- [2-[[(cyclohexylmethyl) amino] carbonyl] -4-fluorophenyl] -1- N-carboxamidine; N- [2-[[(cyclobutylmethyl) amino] carbonyl] -4 · fluorophenyl] -1-carboxamidine; N- [2-[[(cyclohexylmethyl) Amino M group] -6-methoxyphenyl] -1-fluorenecarboxamide; N- [2-amino groups each [[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -1-carboxamide Fluorenamine; N- [2-[[(cyclohexylfluorenyl) amino] M]]-6-methylphenyl] carboxamide; NH- [5-amino-2-[[(cyclo Hexylmethyl) amino] carbonyl] phenyl] _1-carboxamidine; 101539 -12- 200539856 N- [3-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -1-Amidinocarboxamide; Ν- [3-Amino-2-[[(cyclobutylmethyl) amino] carbonyl] phenylamidinocarbamidine; Ν- [2-[[(cyclohexylmethyl Aminyl) amino] quinyl] -3-methylphenyl] -1-fluorencarboxamidine; Ν- [2-[[(cyclohexylmethyl) amino] quinyl] -4,5-dimethyl Oxyphenyl] thermamine; Ν- [2-[[(cyclohexylmethyl) amino] kisyl] -3-methoxy Yl] -1_fluorenecarboxamidine; Ν_ [2-[[(cyclobutylmethyl) amino] quinyl] -3_methoxyphenyl] -1-carboxamidine; Ν- [2-[[ (Cyclohexylmethyl) amino] carbonyl] -3-hydroxyphenyl] -l-carboxamidine; N- [2-[[(cyclobutylmethyl) amino] amido] -3-phenyl ] Berberylcarboxamidine; Ν- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -8-pyridinocarboxamidine; Ν- [4-airyl- 2 _ [[(Cyclohexylmethyl) amino] carbonyl] phenyl] _2_quinolinecarboxamide; N- [4-airyl-2-[[(cyclohexylamido) amino] carbonyl] phenyl ] -2-quinolinoline sulfonamide; Ν- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -1-fluorenecarboxamide; Ν- [4- Gaso-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3-carbolinecarboxamide; N- [4-Gamo-2-[[(cyclohexylmethyl) amino ] Carbonyl] phenyl] -2-pyroxycarboxamide; N- [4-chloroyl-2-[[(cyclohexylfluorenyl) amino] carbonyl] phenyl] -3-carboxoxycarboxamide; Ν- [4-chloroyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-teacarboxamide; Ν- [4-chloroyl-2-[[(cyclohexylmethyl (Amino) amino] carbonyl] phenyl] -4-pyridinecarboxyl 101539 • 13- 200539856 amine; N- [4- Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] _3-pyridinecarboxamide; 2- (benzylideneamino) _5 • Ga (cyclohexylmethyl) _benzidine Amine; N- [4-Chloro-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3,4-dihydro-2H-1,5-benzodioxazepinene -7-carboxamidine; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2,3 · dihydro-7-benzofurancarboxamide; N- [4-chloro-2--2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -1-isoquinolinecarboxamide; N- [4-airyl-2-[[(cyclo Hexylfluorenyl) amino] carbonyl] phenyl] -4-fluorinylcarboxamide; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -4- Fluorolinecarboxamidine; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-methoxy-1-fluorencarboxamidine; Ν- [4 -Amino-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-pyridinecarboxamide; N- [4-airyl-2-[[(cyclohexylmethyl) amine ] Carbonyl] phenyl] -2-fluoro-3--3- (trifluorofluorenyl) -benzamide; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] benzene Yl] -2,3-difluoro-benzylamine; 3-chloro-N- [4-chloro-2-2 [[(cyclohexyl (Methyl) amino] Jinyl] phenyl] -2-fluoro-benzylamine; 101539 -14- 200539856 N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] benzene Phenyl] -2,3-dimethyl-benzylamine; N- [4-chloro-2--2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -3-fluoro-2- (Trifluoromethyl) -benzamide; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2,2-difluoro-1,3- Benzodioxolene-4-carboxamide; N- [4-airyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -6-fluoro-4H-1, 3-Benzodioxolene-8-carboxamide; N- [4-Gastilbene [[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-fluorenyl-3- (tri Fluorofluorenyl) -benzamide; 3-Gas-N- [4-Gasyl-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2-methyl-benzylamine ; N- [4-Gamo-2-[[(cyclohexylmethyl) amino] carbonyl] phenyl] -2,3-dimethoxy-benzidine; N- [4-Gamo- 2-[[(Cyclohexylfluorenyl) amino] carbonyl] phenyl] -3-methoxy-2-fluorenyl-benzylamine; Ν- [4 · 气 基 _2 _ [[(cyclohexylfluorenyl) ) Amino] carbonyl] phenyl] -5-isoquinolinecarboxamide; 6-Ga-N- [4-Gamo_2-[[(cyclohexylmethyl (Amino) amino group M] phenyl] -2-fluoro-3-methyl-benzylamine; 2-amino-N- [4-airyl-2-[[(cyclohexylfluorenyl) amino) ] Weiji] phenyl] -3- (trifluorofluorenyl) -phenylhydrazine; N- [4-airyl · 2-[[(cyclohexylfluorenyl) amino] carbonyl] benzyl] -5 -Porphyrin Carboxamide; 101539 • 15- 200539856 N- [2-[[(Cyclohexylmethyl) aminomethyl] _4-methoxyphenylη • naphthylcarboxamide; Ν_ (3-methoxy _2-{[(2-hexahydropyridine-1_ylethyl) amino] carbonyl} phenyl) + amine naphthoate; Ν_ (2-{[((1,4-dioxolidine-2- Fluorenyl) amino] amino} -3-methoxyphenyl) -1_fluorenamine; N- (3-fluorenyloxy_2 _ {[(2-morpholine-4-ylethyl) Amine] carbonyl} phenyl) berberamine; N- (3-methoxytoluene {[(2-tetrahydropyrrole-1-ylethyl) amino] carbonyl} phenyl) -i-tea Amidoamine; N- {3-methoxy-2 _ [(tetrahydro-2H-piperan-4-ylamino) carbonyl] phenylbutan-1-amine; 3-({[2- [ Oxy-6- (1-methylformamidinylamino) benzylidene] amino} methyl) morpholine-4-carboxylic acid tert-butyl ester; Ν- {2-[(1-nitrogen Bicyclo [2.2.2] oct-3-ylamino) carbonyl] _3_fluorenylphenyl} · 1-naphthylamine Ν- (3-methoxy-2-{[(morpholine-3-ylmethyl) amino] carbonyl} phenyl) berberamine; Ν- {3-methoxy · 2 _ [( Morpholine-4-ylamino) carbonyl] phenyl} berberamine; N- {3-methoxy-2-[(hexahydropyridin-1-ylamino) carbonyl] phenyl} small Fluorenamine; Ν- (2-{[(2-hydroxyethyl) amino] carbonyl} -3-methoxyphenyl) berberamine; Ν- (2-{[(2-hydroxypropyl ) Amino] carbonyl} -3-fluorenoxyphenyl) -1-methylcarboxamide; N- (2-{[((2-hydroxybutyl) aminoboryl} _3_methoxyphenyl) -1 _Metrazidine; 101539 -16- 200539856 and its pharmaceutically acceptable salts. 10. The compound according to any one of claims 1 &, force, and 9, which is used as a medicament. The use of the compound of any of the female formulas of the item 丨 -9 in the manufacture of a medicament for the treatment of pain. 12. Use of a compound according to any one of items 1 to 9 in May in the manufacture of a medicament for the treatment of a functional gastrointestinal disorder. 13·種如凊求項1-9中任一項之化合物於藥劑製造上之用 途，該藥劑係用於治療刺激性腸徵候簇。 14· 一種如請求項丨_9中任一項之化合物於藥劑製造上之用 途，忒藥劑係用於治療焦慮、癌症、多發性硬化、巴金生 氏病、亨丁頓氏舞蹈症、阿耳滋海默氏疾病及心血管病症。 15·-種醫藥組合物，其包含如請求項w中任一項之化合物 及藥學上可接受載劑。13. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for treating irritating bowel syndrome. 14. · Use of a compound according to any one of the claims 丨 _9 in the manufacture of a medicament, which is used to treat anxiety, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Aer Zheimer's disease and cardiovascular disorders. 15. A pharmaceutical composition comprising a compound according to any one of claim w and a pharmaceutically acceptable carrier. 16. —種製備式I化合物之方法16. —Method for preparing compound of formula I 其包括使式11化合物 〇This includes using a compound of formula 11 OR π 101539 -17· 200539856 與R3 (CH2)nR4NH化合物，於鹼譬如DIPEA，溶劑譬如DMF， 及視情況選用之偶合試劑譬如HATU存在下反應之步驟， 其中： m係選自〇, 1及2 ; 11係選自0，1，2,3,4及5; R1係獨立選自鹵素、氰基、胺基、硝基、Ci 6烷胺基、 二Ci_6烷胺基、乙醯胺基、羥基、Ci 6烷氧基、c^6烷基、 鹵化Ci-6烧氧基、（^-6烯基及齒化Cl-6烷基； R2係選自Cno芳基與〇：2-1〇雜環基；其中該用於定義化2 之Cno芳基與（：2_10雜環基，係視情況被一或多個基團取 代，該基團係選自齒素、齒化Ci-6烷基、Ci-6烷基、氰基、 硝基、q·6烷氧基、鹵化Ci6烷氧基、羥基、羥基名16烷 基、胺基、烷氧基-(^-6烷基、Ci-6烷羰基、（^-6烷氧羰 基、Ch烷胺基、二c1-6烷基胺基、胺基烷基、C2-5 雜環基-Ch烷基、C3-6環烷基、C2-6雜芳基、雜芳基_Ci6 烷基、C6-10芳基及C6-10芳基 <卜6烷基；且 R3係選自氫與C^6烷基；R4係選自Ci 6烷基、C3 7環烷 基、c4-7環烯基、c6-10芳基、C2-6雜環基_胺基、C2 6雜環 基氧基-胺基及（：2_6雜環基；其中該用於定義圮之^ —烷 基、C：3·7環烷基、（：4·7環烯基、（^1〇芳基、c26雜環基_胺 基、C2-6雜環基氧基-胺基及C26雜環基，係視情況被一或 多個基團取代，該基團係選自鹵素、鹵化Ci_6烷基、 烷基、氰基、硝基、Ci-6烷氧基、鹵化Ci 6烷氧基、羥基、 羥基-Ch烷基、胺基、Cl_6烷氧基心16烷基、Ci_6烷羰基、 101539 -18 - 200539856 Cu烷氧羰基、Cu烷胺基、二Ci 6烷基_胺基、胺基七卜6 烷基、C3_6環烷基、C2-6雜芳基、雜芳基七16烷基、C6-10 J N/(CH2)n_r4 芳基及C6-10芳基-Cl_6烧基；或$、R3 係選自c2-1〇雜 環基，其係視情況被一或多個基團取代，該基團係選自鹵 素 _素取代之Ci - 6烧基、Ci - 6烧基、氰基、硝基、Q - 6 烧氧基、鹵化q-6烷氧基、羥基、羥基-Q-6烷基、胺基、 Cl-6燒氧基-Q-6烷基、（^-6烷羰基、（^-6烷氧羰基、（^-6烷 胺基、二Ci-6烷基-胺基、胺基-Q-6烷基、C3_6環烷基、C2-6 雜芳基、雜芳基-Cu烷基、C6-1()芳基及C6-10芳基-Ci-6烷 基0 101539 -19 - 200539856 七、指定代表圖·· (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：OR π 101539 -17 · 200539856 and R3 (CH2) nR4NH compound, the reaction step in the presence of a base such as DIPEA, a solvent such as DMF, and optionally a coupling reagent such as HATU, where: m is selected from 0, 1 and 2 11 is selected from 0,1,2,3,4 and 5; R1 is independently selected from halogen, cyano, amine, nitro, Ci 6 alkylamino, di Ci-6 alkylamino, acetamido, Hydroxyl, Ci 6 alkoxy, c ^ 6 alkyl, halogenated Ci-6 alkoxy, (^ -6 alkenyl, and dendritic Cl-6 alkyl; R2 is selected from Cnoaryl and 0: 2-1 〇 Heterocyclyl; where the Cno aryl group used to define Hua 2 and (: 2-10 heterocyclic group are optionally substituted by one or more groups, the group is selected from the group consisting of dentin and dentin Ci-6 Alkyl, Ci-6 alkyl, cyano, nitro, q · 6 alkoxy, halogenated Ci6 alkoxy, hydroxy, hydroxy name 16 alkyl, amino, alkoxy-(^-6 alkyl, Ci-6 alkylcarbonyl, (^ -6 alkoxycarbonyl, Ch alkylamino, dic1-6 alkylamino, aminoalkyl, C2-5 heterocyclyl-Chalkyl, C3-6 cycloalkyl , C2-6 heteroaryl, heteroaryl_Ci6 alkyl, C6-10 aryl, and C6-10 aryl < 6 alkyl; and R3 is selected from hydrogen C ^ 6 alkyl; R4 is selected from Ci 6 alkyl, C 3 7 cycloalkyl, c 4-7 cycloalkenyl, c 6-10 aryl, C 2-6 heterocyclyl-amino, C 2 6 heterocyclyl oxygen -Amino group and (: 2-6 heterocyclic group; where this is used to define ^-alkyl, C: 3 · 7 cycloalkyl, (: 4 · 7 cycloalkenyl, (^ 10 aryl, c26 Heterocyclyl-amino, C2-6 heterocyclyloxy-amino and C26 heterocyclyl, optionally substituted by one or more groups, the group is selected from halogen, Ci-6 alkyl halide, alkane Group, cyano, nitro, Ci-6 alkoxy, halogenated Ci 6 alkoxy, hydroxy, hydroxy-Ch alkyl, amino, Cl_6 alkoxy, hexaalkyl, Ci_6 alkylcarbonyl, 101539 -18- 200539856 Cu alkoxycarbonyl, Cu alkylamino, di Ci 6 alkyl-amine, amine hept 6 alkyl, C 3-6 cycloalkyl, C 2-6 heteroaryl, heteroaryl hex 16 alkyl, C6- 10 JN / (CH2) n_r4 aryl group and C6-10 aryl-Cl_6 alkyl group; or $, R3 is selected from the group consisting of c2-1o heterocyclic group, which is optionally substituted by one or more groups, the group The group is selected from Ci-6 alkyl, Ci-6 alkyl, cyano, nitro, Q-6 alkyloxy, halogenated q-6 alkoxy, hydroxyl, -Q-6 alkyl, amine, Cl-6 alkoxy-Q-6 alkyl, (^ -6 alkylcarbonyl, (^ -6 alkoxycarbonyl, (^ -6 alkylamino, di Ci- 6 alkyl-amino, amine-Q-6 alkyl, C3-6 cycloalkyl, C2-6 heteroaryl, heteroaryl-Cu alkyl, C6-1 () aryl, and C6-10 aryl- Ci-6 alkyl group 0 101539 -19-200539856 VII. Designated representative map ... (1) The designated representative map of this case is: (none) (II) The component symbols of this representative map are simply explained: 8. If the case has a chemical formula, Please reveal the chemical formula that best characterizes the invention: 101539101539
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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2008015214A (en) 2006-05-31 2008-12-12 Abbott Lab Compounds as cannabinoid receptor ligands and uses thereof.
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
CA2681586A1 (en) 2007-03-28 2008-10-09 Abbott Laboratories 1, 3-thiazol-2 (3h) -ylidene compounds as cannabinoid receptor ligands
US7872033B2 (en) 2007-04-17 2011-01-18 Abbott Laboratories Compounds as cannabinoid receptor ligands
EP2160393A1 (en) 2007-05-18 2010-03-10 Abbott Laboratories Novel compounds as cannabinoid receptor ligands
US8338623B2 (en) 2007-07-09 2012-12-25 Abbvie Inc. Compounds as cannabinoid receptor ligands
US9193713B2 (en) 2007-10-12 2015-11-24 Abbvie Inc. Compounds as cannabinoid receptor ligands
AU2009203549B2 (en) * 2008-01-08 2013-03-07 Purdue Pharma L.P. Proline Analogs as ligands for cannabinoid receptors for the treatment of pain
US8846730B2 (en) 2008-09-08 2014-09-30 Abbvie Inc. Compounds as cannabinoid receptor ligands
GB2463318A (en) * 2008-09-12 2010-03-17 Syngenta Participations Ag Preparation of anthranilamide derivatives containing a pyridinylpyrazole moiety
ES2556752T3 (en) 2008-09-16 2016-01-20 Abbvie Bahamas Ltd. Cannabinoid receptor ligands
PA8854001A1 (en) 2008-12-16 2010-07-27 Abbott Lab NEW COMPOUNDS AS CANABINOID RECEIVERS LIGANDS
PL2864291T3 (en) 2012-06-26 2017-07-31 Bayer Pharma Aktiengesellschaft N-[4-(quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products
KR20140011780A (en) * 2012-07-19 2014-01-29 한미약품 주식회사 Isoquinoline-5-carboxamide derivatives having inhibitory activity for protein kinases
SG10201900695PA (en) * 2012-12-06 2019-02-27 Baruch S Blumberg Inst Functionalized benzamide derivatives as antiviral agents against hbv infection
GB201313664D0 (en) * 2013-07-31 2013-09-11 Univ Cardiff Bcl-3 inhibitors
WO2016016728A2 (en) * 2014-07-31 2016-02-04 University College Cardiff Consultants Limited Bcl-3 inhibitors
MX2017001553A (en) 2014-08-04 2017-07-24 Nuevolution As Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases.
WO2016115013A1 (en) * 2015-01-12 2016-07-21 Janssen Pharmaceutica Nv Cinnoline derivatives useful as cb-1 receptor inverse agonists
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof
WO2019170543A1 (en) 2018-03-07 2019-09-12 Bayer Aktiengesellschaft Identification and use of erk5 inhibitors
WO2020234103A1 (en) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification and use of kras inhibitors
CN114401935B (en) 2019-12-14 2024-04-05 上海市东方医院（同济大学附属东方医院） Ion channel antagonists/blockers and uses thereof
CA3160522A1 (en) 2019-12-20 2021-06-24 Sanne Schroder Glad Compounds active towards nuclear receptors
WO2021152113A1 (en) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Substituted 2,3-benzodiazepines derivatives
JP2023519603A (en) 2020-03-31 2023-05-11 ヌエヴォリューション・アクティーゼルスカブ Compounds active against nuclear receptors
JP2023519605A (en) 2020-03-31 2023-05-11 ヌエヴォリューション・アクティーゼルスカブ Compounds active against nuclear receptors

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3166627D1 (en) * 1980-12-12 1984-11-15 Thomae Gmbh Dr K Pyrimidones, their preparation and medicines containing them
DK0450097T3 (en) * 1989-10-20 1996-05-20 Otsuka Pharma Co Ltd Benzoheterocyclic Compounds
DE19648793A1 (en) * 1996-11-26 1998-05-28 Basf Ag New benzamides and their application
MY138097A (en) * 2000-03-22 2009-04-30 Du Pont Insecticidal anthranilamides
WO2002010154A2 (en) * 2000-07-27 2002-02-07 Eli Lilly And Company Substituted heterocyclic amides
JP2005520171A (en) * 2001-04-10 2005-07-07 トランス　テック　ファーマ，インコーポレイテッド Probes, systems, and methods for drug discovery
GB0222493D0 (en) * 2002-09-27 2002-11-06 Glaxo Group Ltd Compounds
US20060089398A1 (en) * 2003-03-19 2006-04-27 Gang Liu Isoxazole carboxamide derivatives as ghrelin receptor modulators

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US20090018116A1 (en) 2009-01-15
UY28922A1 (en) 2005-12-30
EP1756044A1 (en) 2007-02-28
AU2005247835A1 (en) 2005-12-08
AR049898A1 (en) 2006-09-13
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MXPA06013536A (en) 2007-01-26

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